Disease Information

General Information of the Disease (ID: DIS00092)

• Name: Ovarian cancer
• ICD: ICD-11: 2C73

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 22 drug(s) in total

Anagrelide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [1]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Anagrelide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Bevacizumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: EPH receptor B4 (EPHB4) [2]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bevacizumab
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Primary pulmonary lymphoepithelioma-like carcinoma tissue; .
• In Vivo Model: Athymic BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: EphB4 was overexpressed in BV-resistant xenograft models instead of other common receptor tyrosine kinases. In addition, when coadministrated with EphB4 blocker NVP-BHG712, the antitumor effect of BV was significantly enhanced in the resistant model, further confirmed the role of EphB4 in BV-resistant ovarian cancer. These results indicate that NVP-BHG712 reverses EphB4 overexpression-mediated resistance to BV.

Butorphanol

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transmembrane protein (TMEFF1) [3]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Butorphanol
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vitro Model: Primary pulmonary lymphoepithelioma-like carcinoma tissue; .
• In Vitro Model: HCK1T cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay; Colony Formation assay; Transwell assay; Flow Cytometry
• Mechanism Description: An important issue with compounds for treating ovarian cancer is the development of drug resistance and side effects. Butorphanol is a synthetic opioid. Opioids have been shown to promote or prevent tumor growth and metastasis. Butorphanol Inhibits the Malignant Biological Behaviors of Ovarian Cancer Cells via Down-Regulating the Expression of TMEFF1.

Carboplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 11 (CASC11) [4]

• Resistant Disease: Ovarian squamous cell carcinoma [ICD-11: 2C73.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of CASC11 in ovarian squamous cell carcinoma mediates the development of cancer cell resistance to chemotherapy (oxaliplatin, tetraplatin, cisplatin, and carboplatin).

Key Molecule: hsa-miR-193b-3p [5]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: 2 platinum-associated miRNAs (miR-193b* and miR-320) that inhibit the expression of five platinum-associated genes (CRIM1, IFIT2, OAS1, kCNMA1 and GRAMD1B). over-expression of miR-193b* in a randomly selected HapMap cell line results in resistance to both carboplatin and cisplatin.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-141 [6]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Key Molecule: hsa-mir-200c [6]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Key Molecule: Tubulin beta-3 chain (TUBB3) [6]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cysteine-rich motor neuron 1 protein (CRIM1) [5]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: 2 platinum-associated miRNAs (miR-193b* and miR-320) that inhibit the expression of five platinum-associated genes (CRIM1, IFIT2, OAS1, kCNMA1 and GRAMD1B). over-expression of miR-193b* in a randomly selected HapMap cell line results in resistance to both carboplatin and cisplatin.

Key Molecule: Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) [5]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: 2 platinum-associated miRNAs (miR-193b* and miR-320) that inhibit the expression of five platinum-associated genes (CRIM1, IFIT2, OAS1, kCNMA1 and GRAMD1B). over-expression of miR-193b* in a randomly selected HapMap cell line results in resistance to both carboplatin and cisplatin.

Key Molecule: Carboxylesterase 4A (CES4A) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.P55S
• Resistant Drug: Carboplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M889K
• Resistant Drug: Carboplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Interleukin 6 receptor (IL6R) [8]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings in the fallopian tube cancer and ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production.

Key Molecule: Interleukin-8 (IL8) [8]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings in the fallopian tube cancer and ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production.

Key Molecule: Interleukin 6 receptor (IL6R) [8]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; .
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings in the fallopian tube cancer and ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production.

Key Molecule: Interleukin-8 (IL8) [8]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carboplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; .
• Experiment for Molecule Alteration: ELISA assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings in the fallopian tube cancer and ovarian cancer cell lines showed that SKOV3 cells displayed 10-fold greater resistance to cisplatin and 5.8 times more resistance to carboplatin than A2780 cells. SKOV3 cells displayed platinum-induced IL-6 and IL-8 overproduction whereas wild type A2780 displayed no detectable cytokine production.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34c-5p [9]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: OVS1 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV-I6 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERk pathway.

Key Molecule: hsa-miR-634 [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Cellular tumor antigen p53 (TP53) [11]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Key Molecule: Pvt1 oncogene (PVT1) [11]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Key Molecule: Metalloproteinase inhibitor 1 (TIMP1) [11]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Amphiregulin (AREG) [9]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: OVS1 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV-I6 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERk pathway.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Growth factor receptor-bound protein 2 (GRB2) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Ribosomal protein S6 kinase alpha-3 (RPS6KA3) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Carboplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutathione S-transferase P (GSTP1) [13]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; .
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 11 (CASC11) [4]

• Resistant Disease: Ovarian squamous cell carcinoma [ICD-11: 2C73.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of CASC11 in ovarian squamous cell carcinoma mediates the development of cancer cell resistance to chemotherapy (oxaliplatin, tetraplatin, cisplatin, and carboplatin).

Key Molecule: hsa-mir-27a [14]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27a acts as an oncogene in ovarian cancer and regulates their proliferation, invasion and chemosensitivity by targeting CUL5.

Key Molecule: hsa-miR-210-3p [15]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR 210 3p regulates cell growth and affects cisplatin sensitivity in human ovarian cancer cells via targeting E2F3.

Key Molecule: hsa-mir-128a [16]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: Long non-protein coding RNA 161 (LINC00161) [16]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: hsa-mir-503 [17]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR503 might be a sensitizer to cisplatin treatment in ovarian cancer by targeting PI3k p85 and participating in the regulation of the PI3k/Akt signaling pathway. The role of miR503 in regulating cisplatin sensitivity in ovarian cancer cells is correlated with the activation of PI3k/Akt signaling.

Key Molecule: hsa-mir-21 [18]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN.

Key Molecule: hsa-miR-199a-3p [19]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR199a/DDR1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: IOSE386 cells; Ovary; Homo sapiens (Human); CVCL_E230
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Wound healing assay
• Mechanism Description: Suppressing miR199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression. Overexpression of miR199a-3p significantly impaired the migratory, invasive, and tumorigenic capabilities of ovarian cancer cells as well as enhanced cisplatin resistance through inhibiting DDR1 expression.

Key Molecule: hsa-miR-30a-5p [20]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: COC1/DDP cells; Ovary; Homo sapiens (Human); CVCL_6892
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: High expression of miRNA-30a-5p was able to promote cell growth and colony forming ability, and enhance cell migration and invasion.

Key Molecule: hsa-miR-509-3p [21]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293A cells; Kideny; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-509-3p expression significantly decreased in patients with platinum-resistance and up-regulation of GOLPH3 and WLS gene expression was observer when cells were transfected with miR-509-3p inhibitor.

Key Molecule: hsa-mir-137 [22]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: c-Myc signaling pathway; Activation; hsa05230
• In Vitro Model: PEO1 cells; Ovary; Homo sapiens (Human); CVCL_2686
• In Vitro Model: PEO4 cells; Ovary; Homo sapiens (Human); CVCL_2690
• In Vivo Model: BALB/c nude mouse xenograft mode; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: In resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin.

Key Molecule: hsa-mir-216a [23]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-216a increases cisplatin resistance in ovarian cancer cells via downregulating PTEN.

Key Molecule: hsa-miR-149-5p [24]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-149-5p promotes the chemoresistance of ovarian cancer cells by directly targeting MST1 and SAV1, leading to the inactivation of Hippo signaling.

Key Molecule: hsa-miR-770-5p [25]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• Experiment for Molecule Alteration: qRT-PCR; ISH
• Experiment for Drug Resistance: Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-770-5p inhibits cisplatin chemoresistance in human ovarian cancer by targeting and reducing the level of ERCC2.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Pvt1 oncogene (PVT1) [26]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: hsa-mir-130a [27]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: hsa-mir-374a [27]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: hsa-miR-21-3p [28]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Several miRNAs that are increased in cisplatin-resistant cells. We show that most of these do not directly contribute to cisplatin resistance. Interestingly, miR-21-3p, the passenger strand of the known oncomiR, directed increased resistance to cisplatin in a range of ovarian cell lines. This effect was specific to the star strand, as miR-21-5p had the opposite effect and actually increased sensitivity of A2780 cells to cisplatin. We identify NAV3 as a potential target of miR-21-3p and show that knockdown of NAV3 increases resistance.

Key Molecule: hsa-mir-128a [29]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Key Molecule: hsa-miR-224-5p [30]

• Resistant Disease: Ovarian papillary serous carcinoma [ICD-11: 2C73.4]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PRKCD signaling pathway; Inhibition; hsa05208
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: PRkCD, known as protein kinase C deta, is a PkC isozyme that acts as a substrate for caspase-3. Its activity is believed to be required for apoptosis induced by DNA damaging agents such as cisplatin, mitomycin C and doxorubicin. miR-224-5p could negatively regulate the expression of PRkCD, and together with PRkCD, they can serve as novel predictors and prognostic biomarkers for OPSC patient response to overall disease-specific survival. The PRkCD pathway may be a molecular mechanism through which miR-224-5p exerts its functions as an oncogene and enhancer of chemoresistance to cisplatin in OPSC patients.

Key Molecule: hsa-mir-21 [31]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JNk1/c-Jun pathway; Activation; hsa04010
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• In Vitro Model: A2780CP20 cells; Ovary; Homo sapiens (Human); CVCL_A5PS
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Alamar blue dye assay
• Mechanism Description: Blocking the JNk-1, the major activator of c-Jun phosphorylation, reduced the expression of pre-mir-21 and increased the expression of its well-known target gene, PDCD4. Overexpression of miR-21 in cisplatin sensitive cells decreased PDCD4 levels and increased cell proliferation. Finally, targeting miR-21 reduced cell growth, proliferation and invasion of cisplatin resistant ovarian cancer cells. These results suggest that the JNk-1/c-Jun/miR-21 pathway contributes to the cisplatin resistance of ovarian cancer cells and demonstrated that miR-21 is a plausible target to overcome cisplatin resistance.

Key Molecule: hsa-mir-489 [32]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: miR-489 is downregulated in cisplatin (CDDP)-resistant ovarian cancer cells, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 overexpression results in an inhibition of SkOV3 and OVCAR3 cell survival and cell growth after CDDP treatment and an induction of cell apoptosis. Inhibition of miR-489 yields the opposite results. In addition, miR-489 overexpression increases the sensitivity of SkOV3/CDDP and OVCAR3/CDDP cells to CDDP and inhibits their colony number. Akt3 is validated as a direct target of miR-489 in SkOV3, OVCAR3, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 inhibited CDDP resistance and cell growth, and promotes apoptosis by suppressing Akt3 expression.

Key Molecule: hsa-miR-199b-5p [33]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JAG1/Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The forced expression of miR-199b-5p could suppress ovarian cancer cell growth and sensitize the cells to cisplatin-induced cytotoxicity. On the other hand, as a direct target of miR-199b-5p in ovarian cancer cells, JAG1 depletion by siRNAs also resulted in cell growth retardation and sensitization to cisplatin-induced cytotoxicity. In contrast, activating Notch1 signaling by JAG1 or repressing miR-199b-5p by anti-miR-199b-5p could induce the activity of JAG1-Notch1 signaling in ovarian cancer cells. The loss of miR-199b-5p increased the activation of JAG1-Notch1 signaling, which in turn promoted ovarian cancer progression and acquired chemoresistance.

Key Molecule: hsa-mir-130a [34], [35]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: miR130a/XIAP signaling pathway; Regulation; hsa05206
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-130a could suppress XIAP expression and sensitize A2780/DDP cells to cisplatin. And finally downstreamtarget validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a knownresistance factor for ovarian cancer.

Key Molecule: hsa-mir-21 [36]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780-CP cells; Ovary; Homo sapiens (Human); CVCL_H745
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The inhibition of miR-21 enhanced the sensitivity of ovarian cancer cells to cisplatin, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, downregulation of PDCD4 results in drug resistance via enhanced expression of c-IAP2 and MDR1.

Key Molecule: hsa-mir-106a [37]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The enhancement of miR-106a expression contributes to the generation of CDDP-resistant ovarian cancer cells, partly by targeting PDCD4. PDCD4 promoted CDDP-induced apoptosis mainly through the death receptor-mediated pathway.

Key Molecule: hsa-mir-106a [38]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown of miR-106a dramatically decreased antiproliferative effects and apoptosis in-duced by cisplatin in A2780 cells, while overexpression of miR-106a significantly increased antiprolif-erative effects and apoptosis induced by cisplatin in A2780/DDP cells. Furthermore, miR-106a inhibited cell survival and cisplatin resistance through downregulating the expression of Mcl-1. Mcl-1 was a di-rect target of miR-106a.

Key Molecule: hsa-mir-29a [39]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-29b [39]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-29c [39]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: hsa-mir-146a [40]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: Higher expression of miR-146a and miR-150 in omental lesions may lead to more aggressive, chemoresistant disease.

Key Molecule: hsa-mir-150 [40]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: Higher expression of miR-146a and miR-150 in omental lesions may lead to more aggressive, chemoresistant disease.

Key Molecule: hsa-mir-141 [41]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780 DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-141 regulates the expression of kEAP1 and that the repression of kEAP1 contributes to cisplatin resistance. Inhibition of NF-kB signaling enhances miR-141-mediated cisplatin sensitivity.

Key Molecule: hsa-mir-130a [42]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT/PTEN/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/CIS cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-130a, acting as an intermediate, might regulate cisplatin resistance by activating PI3k/Akt/PTEN/mTOR and ABC superfamily drug transporter pathways in ovarian cancer cells.

Key Molecule: hsa-mir-93 [43]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Activation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-93, a new family member of PTEN regulator, blocks PTEN translation leading to activation of the AkT pathway and played an important role in regulating cisplatin chemosensitivity pathway in ovarian cancer.

Key Molecule: hsa-mir-125b [44]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bak1 was a direct target of miR-125b, and down-regulation of Bak1 suppressed cisplatin-induced apoptosis and led to an increased resistance to cisplatin. miR-125b has a sig-nificantly promoting effect on chemoresistance of C13* cells and up-regulation of miR-125b expression contributes to cisplatin resistance through suppression of Bak1 expression.

Key Molecule: hsa-mir-376c [45]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Nodal/ALK7 signaling pathway; Inhibition; hsa04350
• Cell Pathway Regulation: Spheroid formation; Activation; hsa04140
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: We found that miR-376c increased cell proliferation and survival, as well as spheroid formation, in part by targeting ALk7. We have also provided evidence that the Nodal-ALk7 pathway is involved in cisplatin-induced ovarian cancer cell death and that miR-376c might promote chemoresistance.

Key Molecule: hsa-mir-214 [46]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-214 induces cell survival and cisplatin resistance through targeting the 3'-untranslated region (UTR) of the PTEN, which leads to down-regulation of PTEN protein and activation of Akt pathway. Inhibition of Akt using Akt inhibitor, API-2/triciribine, or introduction of PTEN cDNA lacking 3'-UTR largely abrogates miR-214-induced cell survival. These findings indicate that deregulation of miRNAs is a recurrent event in human ovarian cancer and that miR-214 induces cell survival and cisplatin resistance primarily through targeting the PTEN/Akt pathway.

Key Molecule: X inactive specific transcript (XIST) [47]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: ALST cells; Ovary; Homo sapiens (Human); CVCL_W778
• In Vitro Model: OVCA432 cells; Ovary; Homo sapiens (Human); CVCL_3769
• In Vitro Model: OVCA 420 cells; Breast; Homo sapiens (Human); CVCL_3935
• In Vitro Model: OVCA3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCA429 cells; Ovary; Homo sapiens (Human); CVCL_3936
• In Vitro Model: OVCA633 cells; Ovary; Homo sapiens (Human); CVCL_W776
• In Vitro Model: OVCA680 cells; Ovary; Homo sapiens (Human); CVCL_W781
• In Vitro Model: OVCA702 cells; Ovary; Homo sapiens (Human); CVCL_W782
• In Vitro Model: OVCA810 cells; Ovary; Homo sapiens (Human); CVCL_W783
• Experiment for Molecule Alteration: qPCR; Microarray assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: One possible down-stream candidate is XIAP, which is the most potent direct inhibitor of caspases and apoptosis among all human IAP family proteins. Down-regulated expression of XIAP has been shown to induce apoptosis in chemoresistant human ovarian cancer cells. Down-regulation of XIST might increase the expression level of XIAP and block drug-induced apoptosis to cause resistance phenotype.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [48]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Owing to the aberrant methylation engendered by DNMT1 over-expression, miR-30a-5p, and miR-30c-5p levels dropped significantly in cisplatin-resistant ovarian cancer (OC) cells. On the contrary, miR-30a/c-5p inhibited Snail and DNMT1 directly. Hence, a feedback loop between DNMT1 and miR-30a/c-5p could be a potential signature for addressing EMT and cisplatin resistance in OC.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [48]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Owing to the aberrant methylation engendered by DNMT1 over-expression, miR-30a-5p, and miR-30c-5p levels dropped significantly in cisplatin-resistant ovarian cancer (OC) cells. On the contrary, miR-30a/c-5p inhibited Snail and DNMT1 directly. Hence, a feedback loop between DNMT1 and miR-30a/c-5p could be a potential signature for addressing EMT and cisplatin resistance in OC.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) []

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We found that EZH2 was overexpressed in cisplatin-resistant ovarian cancer cells compared with cisplatin-sensitive cells. Knockdown of EZH2 by RNA interference (RNAi) resensitized drug-resistant ovarian cancer A2780/DDP cells to cisplatin and decreased the level of H3K27 trimethylation (H3K27me3).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [27]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: ATP-binding cassette sub-family C5 (ABCC5) [29]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [13]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; .
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Zinc finger protein SNAI1 (SNAI1) [49]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells.

Key Molecule: hsa-mir-363 [49]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Snail overexpression could significantly attenuate miR-363-suppressed cisplatin resistance of EOC cells, suggesting that miR-363-regulated cisplatin resistance is mediated by snail-induced EMT in EOC cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cullin-5 (CUL5) [14]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Dual luciferase assay; qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27a acts as an oncogene in ovarian cancer and regulates their proliferation, invasion and chemosensitivity by targeting CUL5.

Key Molecule: Transcription factor E2F3 (E2F3) [15]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR 210 3p regulates cell growth and affects cisplatin sensitivity in human ovarian cancer cells via targeting E2F3.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [16]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Colony formation assays
• Mechanism Description: Linc00161 regulated the drug resistance of ovarian cancer by sponging microRNA-128 and modulating MAPk1.

Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1) [17]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR503 might be a sensitizer to cisplatin treatment in ovarian cancer by targeting PI3k p85 and participating in the regulation of the PI3k/Akt signaling pathway. The role of miR503 in regulating cisplatin sensitivity in ovarian cancer cells is correlated with the activation of PI3k/Akt signaling.

Key Molecule: Phosphatase and tensin homolog (PTEN) [18]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN/PI3K/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-21 enhances chemoresistance to cisplatin in epithelial ovarian cancer by negatively regulating PTEN.

Key Molecule: Epithelial discoidin domain-containing receptor 1 (DDR1) [19]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR199a/DDR1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: IOSE386 cells; Ovary; Homo sapiens (Human); CVCL_E230
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry assay; Luciferase assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis; Wound healing assay
• Mechanism Description: Suppressing miR199a-3p by promoter methylation contributes to tumor aggressiveness and cisplatin resistance of ovarian cancer through promoting DDR1 expression. Overexpression of miR199a-3p significantly impaired the migratory, invasive, and tumorigenic capabilities of ovarian cancer cells as well as enhanced cisplatin resistance through inhibiting DDR1 expression.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [21]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Regulation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293A cells; Kideny; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-509-3p expression significantly decreased in patients with platinum-resistance and up-regulation of GOLPH3 and WLS gene expression was observer when cells were transfected with miR-509-3p inhibitor.

Key Molecule: Protein wntless homolog (WLS) [21]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Regulation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293A cells; Kideny; Homo sapiens (Human); CVCL_6910
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-509-3p expression significantly decreased in patients with platinum-resistance and up-regulation of GOLPH3 and WLS gene expression was observer when cells were transfected with miR-509-3p inhibitor.

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [22]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: c-Myc/miR137/EZH2 signaling pathway; Regulation; hsa05206
• In Vitro Model: PEO1 cells; Ovary; Homo sapiens (Human); CVCL_2686
• In Vitro Model: PEO4 cells; Ovary; Homo sapiens (Human); CVCL_2690
• In Vivo Model: BALB/c nude mouse xenograft mode; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: SRB assay
• Mechanism Description: In resistant cells c-Myc enhances the expression of EZH2 by directly suppressing miR-137 that targets EZH2 mRNA, and increased expression of EZH2 activates cellular survival pathways, resulting in the resistance to cisplatin.

Key Molecule: Phosphatase and tensin homolog (PTEN) [23]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-216a increases cisplatin resistance in ovarian cancer cells via downregulating PTEN.

Key Molecule: Serine/threonine-protein kinase 4 (MST1) [24]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-149-5p promotes the chemoresistance of ovarian cancer cells by directly targeting MST1 and SAV1, leading to the inactivation of Hippo signaling.

Key Molecule: Protein salvador homolog 1 (SAV1) [24]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Hippo signaling pathway; Inhibition; hsa04390
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-149-5p promotes the chemoresistance of ovarian cancer cells by directly targeting MST1 and SAV1, leading to the inactivation of Hippo signaling.

Key Molecule: General transcription and DNA repair factor IIH helicase subunit XPD (ERCC2) [25]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• Experiment for Molecule Alteration: CASP comet analysis
• Experiment for Drug Resistance: Flow cytometry assay; TUNEL assay
• Mechanism Description: miR-770-5p inhibits cisplatin chemoresistance in human ovarian cancer by targeting and reducing the level of ERCC2.

Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutamate--cysteine ligase catalytic subunit (GCLC) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutamate--cysteine ligase regulatory subunit (GCLM) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Glutathione reductase (GSR) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Quinone reductase 1 (NQO1) [12]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating Glutathione Metabolism in High-Grade Serous Ovarian Cancer.Additionally, we verified that different H19 expression levels in HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins, including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione metabolism pathway, were reduced in H19-knockdown cells. Furthermore, H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment and exhibited lower glutathione levels. Our results reveal a previously unknown link between H19 and glutathione metabolism in the regulation of cancer-drug resistance.

Key Molecule: Caspase-3 (CASP3) [26]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: Mothers against decapentaplegic homolog 4 (SMAD4) [26]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: Transforming growth factor beta 1 (TGFB1) [26]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vitro Model: SkOV-3/DDP cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: PVT1 was overexpressed in tumor tissues of cisplatin-resistant patients comparing to cisplatin-sensitive patients. PVT1 knockdown significantly lowered cell viability and increased the percentage of apoptotic tumor cells in SkOV-3/DDP and A2780/DDP cells transfected with siPVT1 and treated with cisplatin. It manifested PVT1 knockdown can reverses the cisplatin resistance in cisplatin-resistant cell lines.

Key Molecule: Phosphatase and tensin homolog (PTEN) [27]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: miR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR-130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression. In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression.

Key Molecule: Neuron navigator 3 (NAV3) [28]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Several miRNAs that are increased in cisplatin-resistant cells. We show that most of these do not directly contribute to cisplatin resistance. Interestingly, miR-21-3p, the passenger strand of the known oncomiR, directed increased resistance to cisplatin in a range of ovarian cell lines. This effect was specific to the star strand, as miR-21-5p had the opposite effect and actually increased sensitivity of A2780 cells to cisplatin. We identify NAV3 as a potential target of miR-21-3p and show that knockdown of NAV3 increases resistance.

Key Molecule: Polycomb complex protein BMI-1 (BMI1) [29]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: PEO14 cells; Ovary; Homo sapiens (Human); CVCL_2687
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-128 resensitized SkOV3/CP cells to cisplatin and reduced the expression of cisplatin-resistant-related proteins ABCC5 and Bmi-1.

Key Molecule: Protein kinase C delta type (PRKCD) [30]

• Resistant Disease: Ovarian papillary serous carcinoma [ICD-11: 2C73.4]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PRKCD signaling pathway; Inhibition; hsa05208
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: PRkCD, known as protein kinase C deta, is a PkC isozyme that acts as a substrate for caspase-3. Its activity is believed to be required for apoptosis induced by DNA damaging agents such as cisplatin, mitomycin C and doxorubicin. miR-224-5p could negatively regulate the expression of PRkCD, and together with PRkCD, they can serve as novel predictors and prognostic biomarkers for OPSC patient response to overall disease-specific survival. The PRkCD pathway may be a molecular mechanism through which miR-224-5p exerts its functions as an oncogene and enhancer of chemoresistance to cisplatin in OPSC patients.

Key Molecule: Programmed cell death protein 4 (PDCD4) [31]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JNk1/c-Jun pathway; Activation; hsa04010
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• In Vitro Model: A2780CP20 cells; Ovary; Homo sapiens (Human); CVCL_A5PS
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Alamar blue dye assay
• Mechanism Description: Blocking the JNk-1, the major activator of c-Jun phosphorylation, reduced the expression of pre-mir-21 and increased the expression of its well-known target gene, PDCD4. Overexpression of miR-21 in cisplatin sensitive cells decreased PDCD4 levels and increased cell proliferation. Finally, targeting miR-21 reduced cell growth, proliferation and invasion of cisplatin resistant ovarian cancer cells. These results suggest that the JNk-1/c-Jun/miR-21 pathway contributes to the cisplatin resistance of ovarian cancer cells and demonstrated that miR-21 is a plausible target to overcome cisplatin resistance.

Key Molecule: RAC-gamma serine/threonine-protein kinase (AKT3) [32]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay
• Mechanism Description: miR-489 is downregulated in cisplatin (CDDP)-resistant ovarian cancer cells, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 overexpression results in an inhibition of SkOV3 and OVCAR3 cell survival and cell growth after CDDP treatment and an induction of cell apoptosis. Inhibition of miR-489 yields the opposite results. In addition, miR-489 overexpression increases the sensitivity of SkOV3/CDDP and OVCAR3/CDDP cells to CDDP and inhibits their colony number. Akt3 is validated as a direct target of miR-489 in SkOV3, OVCAR3, SkOV3/CDDP and OVCAR3/CDDP cells. miR-489 inhibited CDDP resistance and cell growth, and promotes apoptosis by suppressing Akt3 expression.

Key Molecule: Protein jagged-1 (JAG1) [33]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: JAG1/Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The forced expression of miR-199b-5p could suppress ovarian cancer cell growth and sensitize the cells to cisplatin-induced cytotoxicity. On the other hand, as a direct target of miR-199b-5p in ovarian cancer cells, JAG1 depletion by siRNAs also resulted in cell growth retardation and sensitization to cisplatin-induced cytotoxicity. In contrast, activating Notch1 signaling by JAG1 or repressing miR-199b-5p by anti-miR-199b-5p could induce the activity of JAG1-Notch1 signaling in ovarian cancer cells. The loss of miR-199b-5p increased the activation of JAG1-Notch1 signaling, which in turn promoted ovarian cancer progression and acquired chemoresistance.

Key Molecule: Programmed cell death protein 4 (PDCD4) [36], [37]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: A2780-CP cells; Ovary; Homo sapiens (Human); CVCL_H745
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The inhibition of miR-21 enhanced the sensitivity of ovarian cancer cells to cisplatin, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, downregulation of PDCD4 results in drug resistance via enhanced expression of c-IAP2 and MDR1. And the enhancement of miR-106a expression contributes to the generation of CDDP-resistant ovarian cancer cells, partly by targeting PDCD4. PDCD4 promoted CDDP-induced apoptosis mainly through the death receptor-mediated pathway.

Key Molecule: Phosphatase and tensin homolog (PTEN) [42], [43], [46]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT/PTEN/mTOR signaling pathway; Activation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: SkOV3/CIS cells; Ovary; Homo sapiens (Human); CVCL_UI88
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-93, a new family member of PTEN regulator, blocks PTEN translation leading to activation of the AkT pathway and played an important role in regulating cisplatin chemosensitivity pathway in ovarian cancer.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [38]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown of miR-106a dramatically decreased antiproliferative effects and apoptosis in-duced by cisplatin in A2780 cells, while overexpression of miR-106a significantly increased antiprolif-erative effects and apoptosis induced by cisplatin in A2780/DDP cells. Furthermore, miR-106a inhibited cell survival and cisplatin resistance through downregulating the expression of Mcl-1. Mcl-1 was a di-rect target of miR-106a.

Key Molecule: Collagen alpha-1(I) chain (COL1A1) [39]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CP70 cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HeyC2 cells; Ovary; Homo sapiens (Human); CVCL_X009
• In Vivo Model: NOD/SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown of miR-29a/b/c increased the ability of cells to escape cisplatin-induced cell death partly through upregulation of collagen type I alpha 1 (COL1A1) and increased the activation of extracellular signal-regulated kinase 1/2 and inactivation of glycogen synthase kinase 3 beta.

Key Molecule: Kelch-like ECH-associated protein 1 (KEAP1) [41]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780 DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-141 regulates the expression of kEAP1 and that the repression of kEAP1 contributes to cisplatin resistance. Inhibition of NF-kB signaling enhances miR-141-mediated cisplatin sensitivity.

Key Molecule: Bcl-2 homologous antagonist/killer (BAK1) [44]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bak1 was a direct target of miR-125b, and down-regulation of Bak1 suppressed cisplatin-induced apoptosis and led to an increased resistance to cisplatin. miR-125b has a sig-nificantly promoting effect on chemoresistance of C13* cells and up-regulation of miR-125b expression contributes to cisplatin resistance through suppression of Bak1 expression.

Key Molecule: Activin receptor-like kinase 7 (ALK7) [45]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Nodal/ALK7 signaling pathway; Inhibition; hsa04350
• In Vitro Model: A2780s cells; Ovary; Homo sapiens (Human); CVCL_4863
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: We found that miR-376c increased cell proliferation and survival, as well as spheroid formation, in part by targeting ALk7. We have also provided evidence that the Nodal-ALk7 pathway is involved in cisplatin-induced ovarian cancer cell death and that miR-376c might promote chemoresistance.

Key Molecule: Macrophage colony-stimulating factor 1 (MCSF) [34]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CIS cells; Ovary; Homo sapiens (Human); CVCL_1942
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Finally downstreamtarget validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a knownresistance factor for ovarian cancer.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [47]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: ALST cells; Ovary; Homo sapiens (Human); CVCL_W778
• In Vitro Model: OVCA432 cells; Ovary; Homo sapiens (Human); CVCL_3769
• In Vitro Model: OVCA 420 cells; Breast; Homo sapiens (Human); CVCL_3935
• In Vitro Model: OVCA3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCA429 cells; Ovary; Homo sapiens (Human); CVCL_3936
• In Vitro Model: OVCA633 cells; Ovary; Homo sapiens (Human); CVCL_W776
• In Vitro Model: OVCA680 cells; Ovary; Homo sapiens (Human); CVCL_W781
• In Vitro Model: OVCA702 cells; Ovary; Homo sapiens (Human); CVCL_W782
• In Vitro Model: OVCA810 cells; Ovary; Homo sapiens (Human); CVCL_W783
• Experiment for Molecule Alteration: Combined immunostaining and chromosome painting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: One possible down-stream candidate is XIAP, which is the most potent direct inhibitor of caspases and apoptosis among all human IAP family proteins. Down-regulated expression of XIAP has been shown to induce apoptosis in chemoresistant human ovarian cancer cells. Down-regulation of XIST might increase the expression level of XIAP and block drug-induced apoptosis to cause resistance phenotype.

Key Molecule: Zinc finger E-box-binding homeobox 2 (ZEB2) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.Y663C
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Retinoblastoma-associated protein (RB1) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.E580X
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Angiogenic potential; Inhibition; hsa04370
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Retinoblastoma-associated protein (RB1) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.E580X
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Matrix protein P1 (HSPD1) [50]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulations of PkM2 and HSPD1 involved in MDR in ovarian cancer.

Key Molecule: Pyruvate kinase M2 (PKM) [50]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: COC1 cells; Ovary; Homo sapiens (Human); CVCL_6891
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Down-regulations of PkM2 and HSPD1 involved in MDR in ovarian cancer.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [51]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vitro Model: OVCAR4 cells; Ovary; Homo sapiens (Human); CVCL_1627
• In Vitro Model: CH1 cells; Abdomen; Homo sapiens (Human); CVCL_D177
• In Vitro Model: 41M cells; Ascites; Homo sapiens (Human); CVCL_4993
• In Vitro Model: PXN94 cells; Pelvis; Homo sapiens (Human); CVCL_4994
• In Vitro Model: HX62 cells; Esophagus; Homo sapiens (Human); CVCL_4995
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: ATP cell viability assay
• Mechanism Description: CCND1 may induce cisplatin resistance both through cell cycle control and inhibition of cellular apoptosis pathways, which have been previously observed37 and supported by our CCND1 knockdown study. The role of CCND1 in cell cycle control is well documented. CCND1 accumulates in cells at middle and late G1 phase and stimulate G1 progression to S phase. The proportion of parental cells in G1/0 correlated with the cisplatin sensitivity, with 833K cells having the highest G1/0 population cells and lowest EC50 value and GCT27 the lowest G1/0 population but highest EC50 score.

Key Molecule: Pyruvate dehydrogenase kinase 2 (PDK2) [52]

• Resistant Disease: Ovarian clear cell Carcinoma [ICD-11: 2C73.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: RMG5 cells; Skin; Homo sapiens (Human); N.A.
• In Vitro Model: RMG1 cells; Ovary; Homo sapiens (Human); CVCL_1662
• In Vivo Model: ICR/nu female mice model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; Western blotting assay
• Experiment for Drug Resistance: WST-8 assay
• Mechanism Description: Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species.

Key Molecule: GSK3B interacting protein (GSKIP) [13]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; .
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [53]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-509-3p [54]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT and DAPI assays
• Mechanism Description: miR509-3p could sensitize ovarian cancer cells to cisplatin treatment by targeting multiple anti-apoptosis genes including BCL2 and promoteing apoptosis in cancer cells.

Key Molecule: hsa-mir-708 [55]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF2BP1/AKT signaling pathway; Inhibition; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Caspase-3 activity assay
• Mechanism Description: miR708 increases the susceptibility of ovarian cancer cells to cisplatin by targeting IGF2BP1 and inhibiting Akt signaling. miR708 downregulated the expression of IGF2BP1 and suppressed Akt phosphorylation. Silencing of IGF2BP1 markedly blocked the phosphorylation of Akt.

Key Molecule: hsa-miR-146a-5p [56]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Dual-luciferase assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA 146a 5p enhances cisplatin induced apoptosis in ovarian cancer cells by targeting multiple anti apoptotic genes, including XIAP, BCL2L2 and BIRC5 via their 3'UTRs.

Key Molecule: hsa-miR-490-3p [57]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: SkOV3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_D622
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR490-3p sensitizes ovarian cancer cells to cisplatin by directly targeting ABCC2. miR490-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ABCC2 expression.

Key Molecule: hsa-mir-216b [58]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_D622
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay; CCK8 assay
• Mechanism Description: miR216b increases cisplatin sensitivity in ovarian cancer cells by targeting PARP1.

Key Molecule: hsa-miR-30a-5p [59]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells.

Key Molecule: hsa-miR-30c-5p [59]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells.

Key Molecule: hsa-miR-595 [60]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: FTE187 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: HG-SOC cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: HO8910PM cells; Ovary; Homo sapiens (Human); CVCL_0310
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-595 sensitizes ovarian cancer cells to cisplatin by targeting ABCB1. The expression level of ABCB1 was inversely correlated with miR595 in the ovarian cancer tissues, overexpression of ABCB1 decreased the miR595-overexpressing HO8910PM and SkOV-3 cell sensitivity to cisplatin.

Key Molecule: hsa-mir-551b [61]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 8910 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay
• Mechanism Description: Down-regulation of Foxo3 and TRIM31 by miR551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer.

Key Molecule: hsa-miR-139-5p [62], [63]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: c-Jun/BCL-xl signaling pathway; Regulation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Recovery of miR-139-5p suppressed the expression of c-Jun and thus reversed cisplatin-resistance in ovarian cancer. And miR-139-5p overexpression combined with inactivation of the MAPk signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2.

Key Molecule: hsa-mir-200b [64]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: hsa-mir-200c [64]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: hsa-miR-142-5p [65]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-142-5p decreases cisplatin IC50 in OVCAR3 and SkOV3 ovarian cancer cells via downregulating XIAP.

Key Molecule: hsa-miR-378a-3p [66]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-378a-3p sensitizes ovarian cancer cells to cisplatin through downregulating MAPk1/GRB2.

Key Molecule: hsa-mir-514 [67]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Key Molecule: hsa-mir-139 [68]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: SNU119 cells; Ovary; Homo sapiens (Human); CVCL_5014
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of ATP7A/B was up-regulated in cisplatin-resistant ovarian cancer cell lines; miR-139 inversely regulates ATP7A/B expression through direct targeting, and affects ovarian cancer chemoresistance through regulation of ATP7A/B.

Key Molecule: hsa-mir-34 [69]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Soft agar colony formation assay
• Mechanism Description: miR-34a exhibited suppressive effects on OC cells via directly binding and downregulating HDAC1 expression, which subsequently decreased the resistance to cisplatin and suppressed proliferation in OC cells.

Key Molecule: hsa-miR-199a-3p [70]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-199a-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ITGB8 expression.

Key Molecule: hsa-mir-23a [71], [72]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Regulation; hsa04115
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Inhibition of miR-23a expression increases the sensitivity of A2780 cells to cisplatin possibly by inhibiting the negative regulation by miR-23a target genes that causes inhibition of P-gp protein expression.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [12]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780-DR cells; Ovary; Homo sapiens (Human); CVCL_EG64
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: H19 overexpression contributes to cisplatin resistance.

Key Molecule: hsa-mir-30a [73]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; Transwell assay
• Mechanism Description: Overexpression of miR-30a decreases cellular vitality, invasion, plasticity and EMT. ETAR is identified as a direct target of miR-30a, and their expression is inversely correlated in EOC cell lines and human tissue samples. Upregulation of miR-30a re-sensitizes resistant EOC cells to cisplatinum by binding ETAR. Overexpression of miR-30a inhibits tumor growth in cisplatinum-resistant xenografts.

Key Molecule: hsa-mir-186 [74]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Both A2780/DDP and A2780/Taxol cells expressed miR-186 at lower levels than A2780. miR-186 overexpression increased the sensitivity of ovarian cancer cell lines to paclitaxel and cisplatin compared with the negative control or mock cells, miR-186 transfection induced cell apoptosis while anti-miR-186 transfection reduced cell apoptosis, suggesting that miR-186 may inhibit the development of drug resistance in ovarian cancer cells. miR-186 overexpression may increase the sensitivity of ovarian cancer cells to paclitaxel by targeting ABCB1 and modulating GST-Pi.

Key Molecule: hsa-mir-100 [75]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The expression of miR-100 is downregulated in SkOV3/DDP cells. Overexpressing miR-100 may effectively increase the sensitivity to cisplatin of human ovarian epithelial cancer SkOV3/DDP cells and may reverse cisplatin-resistance of EOC (epithelial ovarian cancer).

Key Molecule: hsa-miR-634 [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: hsa-miR-133b [53]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Key Molecule: hsa-mir-506 [76]

• Sensitive Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6-FOXM1 signaling pathway; Regulation; hsa04218
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-506 overexpression sensitized ovarian cancer cells to cisplatin or to a commercially available PARP inhibitor (olaparib) due to miR-506 overexpression decreasing RAD51 levels and homologous recombination efficiency.

Key Molecule: hsa-mir-93 [77]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: There is an elevated expression of DNA polymerase Eta (Pol Eta) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically (+) translesion DNA synthesis (TLS). Down-regulation of Pol Eta blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol Eta-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol Eta expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically (+) Pol Eta-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol Eta, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

Key Molecule: hsa-miR-449a [78]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-8 dye assay; Flow cytometry assay
• Mechanism Description: miR-449a was involved in cisplatin resistance and the overexpression of miR449a increased cisplatin sensitivity mainly through inhibiting proliferation and promoting apoptosis and the direct downregulating the expression of NOTCH1.

Key Molecule: hsa-mir-370 [79]

• Sensitive Disease: Endometrioid ovarian cancer [ICD-11: 2C73.5]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: TOV112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• Experiment for Molecule Alteration: qRT-PCR; Northern blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-370 (miR-370) was down-regulated in endometrioid ovarian cancer cells. In IGROV1 and TOV112D endometrioid ovarian cancer cells, miR-370 suppressed cellular viability and colony formation. miR-370 also (+) endometrioid ovarian cancer cell chemosensitivity to cDDP. Endoglin (ENG) was directly and negatively regulated by miR-370.

Key Molecule: hsa-mir-29b [80]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Key Molecule: hsa-mir-9 [81]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Homologous-recombination; Regulation
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor onset measured
• Mechanism Description: miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells, miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer, improve chemotherapeutic (like cisplatin) efficacy by increasing the sensitivity of cancer cells to DNA damage.

Key Molecule: hsa-mir-103 [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-miR-107 [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-mir-152 [83]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vivo Model: CD-1/CD-1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-152 and miR-185 were involved in cisplatin resistance, miR-152 and miR-185 increased cisplatin sensitivity mainly through the direct downregulation of DNMT1. DNMT1 is the most abundant DNA methyltransferase in mammalian cells and the key enzyme for the maintenance of hemimethylated DNA during DNA replication and de novo methylation during somatic cell development and differentiation. DNMT1 expression is also upregulated in many malignancies.

Key Molecule: hsa-mir-185 [83]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vivo Model: CD-1/CD-1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-152 and miR-185 were involved in cisplatin resistance, miR-152 and miR-185 increased cisplatin sensitivity mainly through the direct downregulation of DNMT1. DNMT1 is the most abundant DNA methyltransferase in mammalian cells and the key enzyme for the maintenance of hemimethylated DNA during DNA replication and de novo methylation during somatic cell development and differentiation. DNMT1 expression is also upregulated in many malignancies.

Key Molecule: hsa-mir-199a [84]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CD44+/CD117+ ovarian CICs cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CD44 plays an important role in cellular adhesion, lymphocyte activation/migration, tumorigenesis, and the formation of metastases, endogenous mature miR-199a may prevent the growth of human ovarian CICs via decreasing the expression of CD44.

Key Molecule: hsa-mir-130b [85]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CSF-1 expression was negatively associated with miR-130b level in ovarian tissues and cell lines. miR-130b modulates MDR by targeting CSF-1, Down-regulation of miR-130b promotes the development of multidrug resistant ovarian cancer partially by targeting the 3'-UTR of CSF-1.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [57]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: SkOV3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_D622
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase assay; Western blot analysis; Immunohistochemical staining assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR490-3p sensitizes ovarian cancer cells to cisplatin by directly targeting ABCC2. miR490-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ABCC2 expression.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [60]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: FTE187 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: HG-SOC cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: HO8910PM cells; Ovary; Homo sapiens (Human); CVCL_0310
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase activity assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-595 sensitizes ovarian cancer cells to cisplatin by targeting ABCB1. The expression level of ABCB1 was inversely correlated with miR595 in the ovarian cancer tissues, overexpression of ABCB1 decreased the miR595-overexpressing HO8910PM and SkOV-3 cell sensitivity to cisplatin.

Key Molecule: ATP-binding cassette sub-family A1 (ABCA1) [67]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Key Molecule: ATP-binding cassette sub-family A10 (ABCA10) [67]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Key Molecule: ATP-binding cassette sub-family F2 (ABCF2) [67]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; colony-formation assay; Soft-agar colony-formation assay
• Mechanism Description: miR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [74]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Both A2780/DDP and A2780/Taxol cells expressed miR-186 at lower levels than A2780. miR-186 overexpression increased the sensitivity of ovarian cancer cell lines to paclitaxel and cisplatin compared with the negative control or mock cells, miR-186 transfection induced cell apoptosis while anti-miR-186 transfection reduced cell apoptosis, suggesting that miR-186 may inhibit the development of drug resistance in ovarian cancer cells. miR-186 overexpression may increase the sensitivity of ovarian cancer cells to paclitaxel by targeting ABCB1 and modulating GST-Pi.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [72]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: The expression of miR-23a in drug-resistance ovarian cancer A2780 cell lines obviously increased; The expression of Runx3 gene could be inhibited by the combination of miR-23a and Runx3 3'UTR domain, which restricted the effect of Runx3 gene on the silence of MDR1 expression; The expression of P-gp in drug-resistance tumor cell was obviously up-regulated, therefore the resistance mechanism was achieved by the classic resistance mechanism; If the expression of miR-23a was inhibited, the regulatory effect decreased, and the expression level of Runx3 increased, and the silent effect of MDR1 expression by Runx3 improved. The expression of P-gp decreased, so the classic resistance mechanism was also inhibited to various degrees, and then the sensitivity of cisplatin to drug-resistance increased.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [53]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Maternally expressed 3 (MEG3) [86]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: MEG3 upregulation can decrease EVs mediated transfer of miR214 in ovarian cancer cells, thereby reducing drug resistance.

Key Molecule: hsa-mir-214 [86]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: MEG3 upregulation can decrease EVs mediated transfer of miR214 in ovarian cancer cells, thereby reducing drug resistance.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [87]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-1294 ameliorated cisplatin-resistant OC malignancy via inhibiting IGF1R.

Key Molecule: hsa-miR-1294 [87]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-1294 ameliorated cisplatin-resistant OC malignancy via inhibiting IGF1R.

Key Molecule: HOX transcript antisense RNA (HOTAIR) [88]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST-8 assay; Flow cytometry assay
• Mechanism Description: The knockdown of HOTAIR using siRNAs with transfection reagent suppressed cell proliferation, reduced the invasion ability of the cells and notably, it restored cisplatin sensitivity of the cisplatin resistant cells specifically by enhancing cisplatin induced cytotoxicity and apoptosis in SkOV 3CDDP/R cells. HOTAIR is required for the maintenance of stemness in cancer cells lines, involving EMT triggering.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [54]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT and DAPI assays
• Mechanism Description: miR509-3p could sensitize ovarian cancer cells to cisplatin treatment by targeting multiple anti-apoptosis genes including BCL2 and promoteing apoptosis in cancer cells.

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) [55]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF2BP1/AKT signaling pathway; Inhibition; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: SkOV3/DDP cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Caspase-3 activity assay
• Mechanism Description: miR708 increases the susceptibility of ovarian cancer cells to cisplatin by targeting IGF2BP1 and inhibiting Akt signaling. miR708 downregulated the expression of IGF2BP1 and suppressed Akt phosphorylation. Silencing of IGF2BP1 markedly blocked the phosphorylation of Akt.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [56]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA 146a 5p enhances cisplatin induced apoptosis in ovarian cancer cells by targeting multiple anti apoptotic genes, including XIAP, BCL2L2 and BIRC5 via their 3'UTRs.

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [56]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA 146a 5p enhances cisplatin induced apoptosis in ovarian cancer cells by targeting multiple anti apoptotic genes, including XIAP, BCL2L2 and BIRC5 via their 3'UTRs.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [56]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA 146a 5p enhances cisplatin induced apoptosis in ovarian cancer cells by targeting multiple anti apoptotic genes, including XIAP, BCL2L2 and BIRC5 via their 3'UTRs.

Key Molecule: Poly[ADP-ribose] synthase 1 (PARP1) [58]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: SkOV3/CDDP cells; Ovary; Homo sapiens (Human); CVCL_D622
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay; CCK8 assay
• Mechanism Description: miR216b increases cisplatin sensitivity in ovarian cancer cells by targeting PARP1.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [59]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells.

Key Molecule: Zinc finger protein SNAI1 (SNAI1) [59]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR30a/c-5p in turn directly inhibited DNMT1 as well as Snail. Forced expression of miR30a/c-5p or knocking down of DNMT1 and Snail promoted cisplatin susceptibility and partially reversed epithelial-mesenchymal transition (EMT) in CP70 cells.

Key Molecule: Forkhead box protein O3 (FOXO3) [61]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 8910 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay
• Mechanism Description: Down-regulation of Foxo3 and TRIM31 by miR551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer.

Key Molecule: E3 ubiquitin-protein ligase TRIM31 (TRIM31) [61]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 8910 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay
• Mechanism Description: Down-regulation of Foxo3 and TRIM31 by miR551b in side population promotes cell proliferation, invasion, and drug resistance of ovarian cancer.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [64]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: DNA (cytosine-5)-methyltransferase 3A (DNMT3A) [64]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: DNA (cytosine-5)-methyltransferase 3B (DNMT3B) [64]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CP cells; Ovary; Homo sapiens (Human); CVCL_0135
• In Vitro Model: HIOSE-80 cells; Ovary; Homo sapiens (Human); CVCL_E274
• In Vitro Model: OV119 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-200b- and miR-200c-mediated downregulation of DNMTs may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [65]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-142-5p decreases cisplatin IC50 in OVCAR3 and SkOV3 ovarian cancer cells via downregulating XIAP.

Key Molecule: Transcription factor Jun (JUN) [63]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: c-Jun/BCL-xl signaling pathway; Regulation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Recovery of miR-139-5p suppressed the expression of c-Jun and thus reversed cisplatin-resistance in ovarian cancer.

Key Molecule: Growth factor receptor-bound protein 2 (GRB2) [66]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-378a-3p sensitizes ovarian cancer cells to cisplatin through downregulating MAPk1/GRB2.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [66]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-378a-3p sensitizes ovarian cancer cells to cisplatin through downregulating MAPk1/GRB2.

Key Molecule: E3 ubiquitin-protein ligase RING2 (RING2) [62]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vivo Model: Nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-139-5p overexpression combined with inactivation of the MAPk signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2.

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [68]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: SNU119 cells; Ovary; Homo sapiens (Human); CVCL_5014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of ATP7A/B was up-regulated in cisplatin-resistant ovarian cancer cell lines; miR-139 inversely regulates ATP7A/B expression through direct targeting, and affects ovarian cancer chemoresistance through regulation of ATP7A/B.

Key Molecule: Copper-transporting ATPase 2 (ATP7B) [68]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: SNU119 cells; Ovary; Homo sapiens (Human); CVCL_5014
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The expression of ATP7A/B was up-regulated in cisplatin-resistant ovarian cancer cell lines; miR-139 inversely regulates ATP7A/B expression through direct targeting, and affects ovarian cancer chemoresistance through regulation of ATP7A/B.

Key Molecule: Histone deacetylase 1 (HDAC1) [69]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Soft agar colony formation assay
• Mechanism Description: miR-34a exhibited suppressive effects on OC cells via directly binding and downregulating HDAC1 expression, which subsequently decreased the resistance to cisplatin and suppressed proliferation in OC cells.

Key Molecule: Integrin beta-8 (ITGB8) [70]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay; Flow cytometry assay
• Mechanism Description: miR-199a-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ITGB8 expression.

Key Molecule: Endothelin-1 receptor (EDNRA) [73]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion method assay; Transwell assay
• Mechanism Description: Overexpression of miR-30a decreases cellular vitality, invasion, plasticity and EMT. ETAR is identified as a direct target of miR-30a, and their expression is inversely correlated in EOC cell lines and human tissue samples. Upregulation of miR-30a re-sensitizes resistant EOC cells to cisplatinum by binding ETAR. Overexpression of miR-30a inhibits tumor growth in cisplatinum-resistant xenografts.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Growth factor receptor-bound protein 2 (GRB2) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Ribosomal protein S6 kinase alpha-3 (RPS6KA3) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [76]

• Sensitive Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6-FOXM1 signaling pathway; Regulation; hsa04218
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Homologous recombination-mediated repair pathway; Inhibition; hsa03440
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-506 overexpression sensitized ovarian cancer cells to cisplatin or to a commercially available PARP inhibitor (olaparib) due to miR-506 overexpression decreasing RAD51 levels and homologous recombination efficiency.

Key Molecule: DNA polymerase theta (POLQ) [77]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: There is an elevated expression of DNA polymerase Eta (Pol Eta) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically (+) translesion DNA synthesis (TLS). Down-regulation of Pol Eta blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol Eta-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol Eta expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically (+) Pol Eta-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol Eta, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

Key Molecule: Runt-related transcription factor 3 (RUNX3) [71]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Regulation; hsa04115
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Inhibition of miR-23a expression increases the sensitivity of A2780 cells to cisplatin possibly by inhibiting the negative regulation by miR-23a target genes that causes inhibition of P-gp protein expression.

Key Molecule: Neurogenic locus notch homolog protein 1 (NOTCH1) [78]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Notch signaling pathway; Inhibition; hsa04330
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-8 dye assay; Flow cytometry assay
• Mechanism Description: miR-449a was involved in cisplatin resistance and the overexpression of miR449a increased cisplatin sensitivity mainly through inhibiting proliferation and promoting apoptosis and the direct downregulating the expression of NOTCH1.

Key Molecule: Endoglin (ENG) [79]

• Sensitive Disease: Endometrioid ovarian cancer [ICD-11: 2C73.5]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: TOV112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA-370 (miR-370) was down-regulated in endometrioid ovarian cancer cells. In IGROV1 and TOV112D endometrioid ovarian cancer cells, miR-370 suppressed cellular viability and colony formation. miR-370 also (+) endometrioid ovarian cancer cell chemosensitivity to cDDP. Endoglin (ENG) was directly and negatively regulated by miR-370.

Key Molecule: Autophagy-related protein 9A (ATG9A) [80]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [81]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Homologous-recombination; Regulation
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vitro Model: C13 cells; Ovary; Homo sapiens (Human); CVCL_0114
• In Vitro Model: OV2008 cells; Ovary; Homo sapiens (Human); CVCL_0473
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemical staining assay
• Experiment for Drug Resistance: Tumor onset measured
• Mechanism Description: miR-9 bound directly to the 3'-UTR of BRCA1 and downregulated BRCA1 expression in ovarian cancer cells, miR-9 mediates the downregulation of BRCA1 and impedes DNA damage repair in ovarian cancer, improve chemotherapeutic (like cisplatin) efficacy by increasing the sensitivity of cancer cells to DNA damage.

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: DNA (cytosine-5)-methyltransferase 1 (DNMT1) [83]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Chemoresistance; Inhibition; hsa05207
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/DDP cells; Ovary; Homo sapiens (Human); CVCL_D619
• In Vivo Model: CD-1/CD-1 nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-152 and miR-185 were involved in cisplatin resistance, miR-152 and miR-185 increased cisplatin sensitivity mainly through the direct downregulation of DNMT1. DNMT1 is the most abundant DNA methyltransferase in mammalian cells and the key enzyme for the maintenance of hemimethylated DNA during DNA replication and de novo methylation during somatic cell development and differentiation. DNMT1 expression is also upregulated in many malignancies.

Key Molecule: Extracellular matrix receptor III (CD44) [84]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CD44+/CD117+ ovarian CICs cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CD44 plays an important role in cellular adhesion, lymphocyte activation/migration, tumorigenesis, and the formation of metastases, endogenous mature miR-199a may prevent the growth of human ovarian CICs via decreasing the expression of CD44.

Key Molecule: Macrophage colony-stimulating factor 1 (MCSF) [85]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CSF-1 expression was negatively associated with miR-130b level in ovarian tissues and cell lines. miR-130b modulates MDR by targeting CSF-1, Down-regulation of miR-130b promotes the development of multidrug resistant ovarian cancer partially by targeting the 3'-UTR of CSF-1.

Key Molecule: Hypoxia-inducible factor 1-alpha (HIF1A) [89]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: PEO1 cells; Ovary; Homo sapiens (Human); CVCL_2686
• In Vitro Model: PEO4 cells; Ovary; Homo sapiens (Human); CVCL_2690
• In Vitro Model: A2780/CP cells; Ovary; Homo sapiens (Human); CVCL_A5PS
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Downregulating hypoxia-inducible factor-1 (HIF-1), which regulates metabolic enzymes involved in glycolysis, is a promising strategy for overcoming cisplatin resistance of human ovarian cancer cells. We found that cisplatin downregulated the level of the regulatable alpha subunit of HIF-1, HIF-1alpha, in cisplatin-sensitive ovarian cancer cells through enhancing HIF-1alpha degradation but did not downregulate HIF-1alpha in their cisplatin-resistant counterparts. Overexpression of a degradation-resistant HIF-1alpha (HIF-1alpha detaODD) reduced cisplatin-induced apoptosis in cisplatin-sensitive cells, whereas genetic knockdown of HIF-1alpha or pharmacological promotion of HIF-1alpha degradation enhanced response to cisplatin in both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells.

Cyclophosphamide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-29b [80]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cyclophosphamide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Autophagy-related protein 9A (ATG9A) [80]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cyclophosphamide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [13]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; .
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27a [14]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27a acts as an oncogene in ovarian cancer and regulates their proliferation, invasion and chemosensitivity by targeting CUL5.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [13]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; .
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cullin-5 (CUL5) [14]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Dual luciferase assay; qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-27a acts as an oncogene in ovarian cancer and regulates their proliferation, invasion and chemosensitivity by targeting CUL5.

Key Molecule: GSK3B interacting protein (GSKIP) [13]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; .
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Efficacy evaluation of chemotherapy
• Mechanism Description: Ovarian cancer tissues had much higher expression levels of MRP1, GST-pai, and GSK3beta mRNA than normal ovarian tissues (P<0.05). The expression levels of MRP1, GST-pai, and GSK3beta mRNA in the Chemotherapy-sensitive group were significantly lower than those in the Chemotherapy-resistant group (P<0.05). Patients with high expression of MRP1, GST-pai, and GSK3beta mRNA had a much lower 3-year survival rate than patients with low expression of the genes (P<0.05). Highly expressed in patients with ovarian cancer, MRP1, GST-pai, and GSK3beta mRNA play an important role in the development and drug resistance of ovarian cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34c-5p [9]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: OVS1 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV-I6 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERk pathway.

Key Molecule: Cellular tumor antigen p53 (TP53) [11]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Key Molecule: Pvt1 oncogene (PVT1) [11]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Key Molecule: Metalloproteinase inhibitor 1 (TIMP1) [11]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 3AO cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: LncRNA PVT1 boost the expression of p53 and TIMP 1 to enhance ovarian cancer cells chemosensitivity for carboplatin and docetaxel.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Amphiregulin (AREG) [9]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: OVS1 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV-I6 cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERk pathway.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein mono-ADP-ribosyltransferase PARP8 (PARP8) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.P81T
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Low-density lipoprotein receptor-related protein 1B (LRP1B) [90]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Structural variation; Copy number loss
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KURAMOCHI cells; Ovary; Homo sapiens (Human); CVCL_1345
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: JHOS3 cells; Ovary; Homo sapiens (Human); CVCL_4648
• In Vitro Model: OVCAR4 cells; Ovary; Homo sapiens (Human); CVCL_1627
• Experiment for Molecule Alteration: High-resolution single-nucleotide polymorphism array assay; Single-cell sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients.

Key Molecule: Low-density lipoprotein receptor-related protein 1B (LRP1B) [90]

• Resistant Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Molecule Alteration: Structural variation; Copy number loss
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: KURAMOCHI cells; Ovary; Homo sapiens (Human); CVCL_1345
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: JHOS3 cells; Ovary; Homo sapiens (Human); CVCL_4648
• In Vitro Model: OVCAR4 cells; Ovary; Homo sapiens (Human); CVCL_1627
• Experiment for Molecule Alteration: High-resolution single-nucleotide polymorphism array assay; Single-cell sequencing assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4) [91]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: CYP450-Glo TM CYP 3A4 assay, RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Key Molecule: Glutathione S-transferase (GST) [91]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: GST colorimetric assay, RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-634 [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: hsa-mir-199a [84]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CD44+/CD117+ ovarian CICs cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CD44 plays an important role in cellular adhesion, lymphocyte activation/migration, tumorigenesis, and the formation of metastases, endogenous mature miR-199a may prevent the growth of human ovarian CICs via decreasing the expression of CD44.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [91]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [91]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [91]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Synergistic interaction between the MDR mechanisms include ABCT proteins (P-gp, BCRP, and MDR1) and metabolic enzymes of phase I of metabolism mainly CYP3A4, phase II of metabolism mainly GST was observed. In this study, FUC alone and in combination with DOX inhibited the enzyme activities of CYP3A4 and GST and down regulated their genes. We interpret this effect as a consequence of a down-regulation of pregnane X receptor (PXR) gene. FUC overcame MDR by significantly suppressing PXR mediated pathways that regulated the expression of CYP3A and ABCB1 genes in HepG-2 cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Growth factor receptor-bound protein 2 (GRB2) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Ribosomal protein S6 kinase alpha-3 (RPS6KA3) [10]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; hsa04010
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-634 is an important player in cisplatin-resistance. First of all, miR-634 was the only miR miR-634 overexpression in ovarian cancer cell lines and patient samples negatively regulates important cell-cycle genes (CCND1) and Ras-MAPk pathway components (GRB2, ERk2, RSk1 and RSk2). Inhibition of the Ras-MAPk pathway resulted in increased sensitivity to cisplatin, suggesting that the miR-634-mediated repression of this pathway is responsible for the effect of miR-634 on cisplatin resistance.

Key Molecule: Extracellular matrix receptor III (CD44) [84]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CD44+/CD117+ ovarian CICs cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CD44 plays an important role in cellular adhesion, lymphocyte activation/migration, tumorigenesis, and the formation of metastases, endogenous mature miR-199a may prevent the growth of human ovarian CICs via decreasing the expression of CD44.

Estradiol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA (RP11-166P13.3) [92]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Up-regulation; Expression
• Resistant Drug: Estradiol
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vivo Model: Male nude mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; RNA pull down assay; FISH assay; RIP experiments assay; Knockdown assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long Non-Coding RNA LINC00511 Mediates the Effects of ESR1 on Proliferation and Invasion of Ovarian Cancer Through miR-424-5p and miR-370-5p.

Key Molecule: Long non-protein coding RNA 511 (LINC00511) [92]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: Estradiol
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vivo Model: Male nude mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; RNA pull down assay; FISH assay; RIP experiments assay; Knockdown assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long Non-Coding RNA LINC00511 Mediates the Effects of ESR1 on Proliferation and Invasion of Ovarian Cancer Through miR-424-5p and miR-370-5p.

Etoposide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-103 [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-miR-107 [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Fluorouracil

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-206 [93]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: As a potential tumor suppressor, miR206 directly targets CDk4 to suppress the cell growth and enhance the chemotherapy sensitivity to 5-Fu in ovarian cancer cells in vitro.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase 4 (CDK4) [93]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: As a potential tumor suppressor, miR206 directly targets CDk4 to suppress the cell growth and enhance the chemotherapy sensitivity to 5-Fu in ovarian cancer cells in vitro.

Ketoprofen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [94]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Function; Inhibition
• Resistant Drug: Ketoprofen
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: A2780/RCIS cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Flow cytometric efflux assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: A new series of quinoline analogs of ketoprofen was designed and synthesized as multidrug resistance protein 2 (MRP2) inhibitors using ketoprofen as the lead compounds.

Lonafarnib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Protein farnesyltransferase subunit beta (FNTB) [95]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Noncoding; (c.7-17904G>C)
• Resistant Drug: Lonafarnib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: electrophoretic-mobility-shift assay; luciferase-reporter assay; RT-qPCR

Mestranol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [1]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Mestranol
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Olaparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-506 [76]

• Sensitive Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Olaparib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6-FOXM1 signaling pathway; Regulation; hsa04218
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Homologous recombination-mediated repair pathway; Inhibition; hsa03440
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-506 overexpression sensitized ovarian cancer cells to cisplatin or to a commercially available PARP inhibitor (olaparib) due to miR-506 overexpression decreasing RAD51 levels and homologous recombination efficiency.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [76]

• Sensitive Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Olaparib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: CDK4/6-FOXM1 signaling pathway; Regulation; hsa04218
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Homologous recombination-mediated repair pathway; Inhibition; hsa03440
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-506 overexpression sensitized ovarian cancer cells to cisplatin or to a commercially available PARP inhibitor (olaparib) due to miR-506 overexpression decreasing RAD51 levels and homologous recombination efficiency.

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 11 (CASC11) [4]

• Resistant Disease: Ovarian squamous cell carcinoma [ICD-11: 2C73.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of CASC11 in ovarian squamous cell carcinoma mediates the development of cancer cell resistance to chemotherapy (oxaliplatin, tetraplatin, cisplatin, and carboplatin).

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [96]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The upregulation of GST-Pi cause excessive intensity of detoxification of cytostatics, affect drug metabolism and influence the effects of chemotherapy, which results in resistance for paclitaxel in the ovarian cancer cells.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-654-5p [97]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MYC/WNT/AKT signaling pathway; Regulation; hsa04217
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: NMRI-nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Time course proliferation assay; Flow cytometry assay
• Mechanism Description: CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AkT pathways.

Key Molecule: hsa-mir-194 [98]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR194. NEAT1 contributed to PTX resistance of ovarian cancer cells at least partly through upregulating ZEB1 expression by sponging miR194.

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [98]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR194. NEAT1 contributed to PTX resistance of ovarian cancer cells at least partly through upregulating ZEB1 expression by sponging miR194.

Key Molecule: hsa-mir-1307 [99]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/Taxol cells; Ovary; Homo sapiens (Human); CVCL_IJ13
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Apoptosis analysis by FITC immunofluorescence
• Mechanism Description: miR1307 promotes ovarian cancer cell chemoresistance by targeting the ING5 expression.

Key Molecule: hsa-miR-194-5p [100]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Down-regulation of miR-194-5p induces paclitaxel resistance in ovarian cancer cells by altering MDM2 expression.

Key Molecule: Urothelial cancer associated 1 (UCA1) [101]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR129/ABCB1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: ABCB1 up-regulated by UCA1/miR-129 axis contributed to PTX resistance in PTX-resistant OC cells.

Key Molecule: hsa-mir-129 [101]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR129/ABCB1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• Experiment for Molecule Alteration: RT-qPCR; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: ABCB1 up-regulated by UCA1/miR-129 axis contributed to PTX resistance in PTX-resistant OC cells.

Key Molecule: hsa-mir-21 [102]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: TGF signaling pathway; Regulation; hsa04350
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: ALST cells; Ovary; Homo sapiens (Human); CVCL_W778
• In Vitro Model: HeyA8-MDR cells; Ovary; Homo sapiens (Human); CVCL_8879
• In Vitro Model: OVCA432 cells; Ovary; Homo sapiens (Human); CVCL_3769
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: SkOV3-TR cells; Ovary; Homo sapiens (Human); CVCL_HF69
• In Vitro Model: SkOV3ip cells; Ovary; Homo sapiens (Human); CVCL_0C84
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The identification of APAF1 as a direct target of miR21 and APAF1 as a mediator of miR21 for conferring chemoresistance in ovarian cancer suggests that strategies based on the upregulation of APAF1 in ovarian cancer cells can be used to sensitize ovarian cancer cells to paclitaxel treatment.ovarian cancer suggests that strategies based on the upregulation of APAF1 in ovarian cancer cells can be used to sensitize ovarian cancer cells to paclitaxel treatment.

Key Molecule: hsa-miR-17-5p [103]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-17-5p induces drug resistance and invasion of ovarian carcinoma cells by targeting PTEN signaling.

Key Molecule: hsa-mir-149 [104]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TLR/MyD88 signaling pathway; Regulation; hsa04620
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: In the present study, flow cytometric assays were used to detect the apoptosis of A2780 cells after down-regulation of miRNA-149. We found that down-regulation of miRNA-149 decreased the apoptosis induced by paclitaxel when compared to the control group. Furthermore, we showed that down-regulation of miRNA-149 in A2780 cells (+) the expression of the anti-apoptotic protein Bcl-2 and inhibited the expression of the pro-apoptotic protein bax, which may have led to paclitaxel resistance.

Key Molecule: hsa-miR-490-3p [96]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: microRNA 490-3P was involved in the development of drug resistance through regulating MDR1/P-gp and GST-Pi expression in ovarian cancer cells.

Key Molecule: hsa-mir-106a [105]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: miR-106a and miR-591 have important roles in conferring PTX resistance to ovarian cancer cells. Modulation of these microRNAs resensitizes PTX-resistant cancer cells by targeting BCL10, caspase-7, and ZEB1.

Key Molecule: hsa-miR-591 [105]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: miR-106a and miR-591 have important roles in conferring PTX resistance to ovarian cancer cells. Modulation of these microRNAs resensitizes PTX-resistant cancer cells by targeting BCL10, caspase-7, and ZEB1.

Key Molecule: hsa-let-7g [106]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vitro Model: LOX-IMVI cells; Ovary; Homo sapiens (Human); CVCL_1381
• In Vitro Model: NCI/ADR-RES cells; Ovary; Homo sapiens (Human); CVCL_1452
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SRB cytotoxicity assay
• Mechanism Description: IMP-1 is an RNA binding protein that acts by stabilizing the mRNA of a number of target genes. In addition, IMP-1 was shown to protect the mRNA of MDR1 from endonucleolytic attack in an in vitro RNA stability assay. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin.

Key Molecule: hsa-mir-135a [107]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN) is a protein that binds to HIF-1alpha and inhibits its transcriptional activity. HIF1AN is a potential miR-135a target listed in both the TargetScan and PicTar databases. miR-135a-mediated paclitaxel resistance is in part mediated by downregulation of APC.

Key Molecule: hsa-mir-27a [108]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miRNAs/HIPk2/MDR1/P-gp signaling pathway; Regulation; hsa05206
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Transfection of A2780/Taxol cells with the inhibitors of miR-27a decreased the expression of MDR1 mRNA and P-gp protein, increased HIPk2 protein expression, enhanced the sensitivity of A2780/taxol cells to paclitaxel, increased paclitaxel-induced apoptosis and the fluorescence intensity of intracellular Rh-123. The deregulation of miR-27a may be involved in the development of drug resistance, regulating the expression of MDR1/P-gp, at least in part, by targeting HIPk2 in ovarian cancer cells.

Key Molecule: hsa-mir-130a [34]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CIS cells; Ovary; Homo sapiens (Human); CVCL_1942
• Experiment for Molecule Alteration: qRT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Finally downstreamtarget validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a knownresistance factor for ovarian cancer.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [101]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR129/ABCB1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: ABCB1 up-regulated by UCA1/miR-129 axis contributed to PTX resistance in PTX-resistant OC cells.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [109]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-181a level in chemoresistant (CR) cancer tissues were significantly higher than in chemosensitive (CS) cancer tissues and in normal tissue. SkOV3/PTX cells had significantly higher expression of miR-181a and N-cadherin than SkOV3 cells. SkOV3 cells had decreased E-cadherin expression and increased N-cadherin expression after enforced miR-181a expression, while SkOV3/PTX cells had increased E-cadherin expression and decreased N-cadherin expression after miR-181a knockdown. SkOV3 cells had increased P-gp expression after enforced miR-181a expression. Following MTT assay and flow cytometry analysis both confirmed that miR-181a overexpression decreased the PTX sensitivity of SkOV3 cells and while miR-181a inhibition increased the sensitivity of SkOV3/PTX cells. miR-181a is an important oncomiR significantly increased in chemoresistant ovarian cancer. Its upregulation is associated with increased level of EMT and decreased cell apoptosis induced by PTX treatment.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [96]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The upregulation of P-gp cause ovarian cancer cells pumping drug substance outside to reduce cytotoxicity presented and enhances the resistance of paclitaxe.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-181a [109]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-181a level in chemoresistant (CR) cancer tissues were significantly higher than in chemosensitive (CS) cancer tissues and in normal tissue. SkOV3/PTX cells had significantly higher expression of miR-181a and N-cadherin than SkOV3 cells. SkOV3 cells had decreased E-cadherin expression and increased N-cadherin expression after enforced miR-181a expression, while SkOV3/PTX cells had increased E-cadherin expression and decreased N-cadherin expression after miR-181a knockdown. SkOV3 cells had increased P-gp expression after enforced miR-181a expression. Following MTT assay and flow cytometry analysis both confirmed that miR-181a overexpression decreased the PTX sensitivity of SkOV3 cells and while miR-181a inhibition increased the sensitivity of SkOV3/PTX cells. miR-181a is an important oncomiR significantly increased in chemoresistant ovarian cancer. Its upregulation is associated with increased level of EMT and decreased cell apoptosis induced by PTX treatment.

Key Molecule: hsa-mir-141 [6]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Key Molecule: hsa-mir-200c [6]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Key Molecule: Tubulin beta-3 chain (TUBB3) [6]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MES-OV cells; Ovary; Homo sapiens (Human); CVCL_CZ92
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: SRB colorimetric assay; Flow cytometry assay
• Mechanism Description: The miR-200 family has major roles in EMT and taxane resistance in taxane selected ovarian cancer cell variants, and that re-introduction of miR-200s was not sufficient to fully reverse the mesenchymal phenotype in these variants. Although miR-200s were able to restore paclitaxel sensitivity in one of the variants, they did not do so in the other, and produced resistance to carboplatin in both. The divergent effects of miR-200s on taxane and carboplatin cytotoxicity should be further investigated in ovarian cancers. miR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: CUB domain-containing protein 1 (CDCP1) [97]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MYC/WNT/AKT signaling pathway; Regulation; hsa04217
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: NMRI-nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Time course proliferation assay; Flow cytometry assay
• Mechanism Description: CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AkT pathways.

Key Molecule: Zinc finger protein PLAGL2 (PLAGL2) [97]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: MYC/WNT/AKT signaling pathway; Regulation; hsa04217
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: NMRI-nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Time course proliferation assay; Flow cytometry assay
• Mechanism Description: CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AkT pathways.

Key Molecule: Growth protein 5 inhibitor (ING5) [99]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780/Taxol cells; Ovary; Homo sapiens (Human); CVCL_IJ13
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Apoptosis analysis by FITC immunofluorescence
• Mechanism Description: miR1307 promotes ovarian cancer cell chemoresistance by targeting the ING5 expression.

Key Molecule: E3 ubiquitin-protein ligase Mdm2 (MDM2) [100]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Down-regulation of miR-194-5p induces paclitaxel resistance in ovarian cancer cells by altering MDM2 expression.

Key Molecule: Apoptotic protease-activating factor 1 (APAF1) [102]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: TGF signaling pathway; Regulation; hsa04350
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: ALST cells; Ovary; Homo sapiens (Human); CVCL_W778
• In Vitro Model: HeyA8-MDR cells; Ovary; Homo sapiens (Human); CVCL_8879
• In Vitro Model: OVCA432 cells; Ovary; Homo sapiens (Human); CVCL_3769
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: SkOV3-TR cells; Ovary; Homo sapiens (Human); CVCL_HF69
• In Vitro Model: SkOV3ip cells; Ovary; Homo sapiens (Human); CVCL_0C84
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Flow cytometric assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The identification of APAF1 as a direct target of miR21 and APAF1 as a mediator of miR21 for conferring chemoresistance in ovarian cancer suggests that strategies based on the upregulation of APAF1 in ovarian cancer cells can be used to sensitize ovarian cancer cells to paclitaxel treatment.ovarian cancer suggests that strategies based on the upregulation of APAF1 in ovarian cancer cells can be used to sensitize ovarian cancer cells to paclitaxel treatment.

Key Molecule: Phosphatase and tensin homolog (PTEN) [103]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PTEN/AKT signaling pathway; Regulation; hsa05235
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: microRNA-17-5p induces drug resistance and invasion of ovarian carcinoma cells by targeting PTEN signaling.

Key Molecule: Myeloid differentiation primary response protein MyD88 (MYD88) [104]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: TLR/MyD88 signaling pathway; Regulation; hsa04620
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell assay
• Mechanism Description: In the present study, flow cytometric assays were used to detect the apoptosis of A2780 cells after down-regulation of miRNA-149. We found that down-regulation of miRNA-149 decreased the apoptosis induced by paclitaxel when compared to the control group. Furthermore, we showed that down-regulation of miRNA-149 in A2780 cells (+) the expression of the anti-apoptotic protein Bcl-2 and inhibited the expression of the pro-apoptotic protein bax, which may have led to paclitaxel resistance.

Key Molecule: B-cell lymphoma/leukemia 10 (BCL10) [105]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: miR-106a and miR-591 have important roles in conferring PTX resistance to ovarian cancer cells. Modulation of these microRNAs resensitizes PTX-resistant cancer cells by targeting BCL10, caspase-7, and ZEB1.

Key Molecule: Caspase-7 (CASP7) [105]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: miR-106a and miR-591 have important roles in conferring PTX resistance to ovarian cancer cells. Modulation of these microRNAs resensitizes PTX-resistant cancer cells by targeting BCL10, caspase-7, and ZEB1.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [105]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: miR-106a and miR-591 have important roles in conferring PTX resistance to ovarian cancer cells. Modulation of these microRNAs resensitizes PTX-resistant cancer cells by targeting BCL10, caspase-7, and ZEB1.

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) [106]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vitro Model: LOX-IMVI cells; Ovary; Homo sapiens (Human); CVCL_1381
• In Vitro Model: NCI/ADR-RES cells; Ovary; Homo sapiens (Human); CVCL_1452
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: SRB cytotoxicity assay
• Mechanism Description: IMP-1 is an RNA binding protein that acts by stabilizing the mRNA of a number of target genes. In addition, IMP-1 was shown to protect the mRNA of MDR1 from endonucleolytic attack in an in vitro RNA stability assay. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin.

Key Molecule: Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN) [107]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Hypoxia-inducible factor 1-alpha inhibitor (HIF1AN) is a protein that binds to HIF-1alpha and inhibits its transcriptional activity. HIF1AN is a potential miR-135a target listed in both the TargetScan and PicTar databases. miR-135a-mediated paclitaxel resistance is in part mediated by downregulation of APC.

Key Molecule: Homeodomain-interacting protein kinase 2 (HIPK2) [108]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miRNAs/HIPk2/MDR1/P-gp signaling pathway; Regulation; hsa05206
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Transfection of A2780/Taxol cells with the inhibitors of miR-27a decreased the expression of MDR1 mRNA and P-gp protein, increased HIPk2 protein expression, enhanced the sensitivity of A2780/taxol cells to paclitaxel, increased paclitaxel-induced apoptosis and the fluorescence intensity of intracellular Rh-123. The deregulation of miR-27a may be involved in the development of drug resistance, regulating the expression of MDR1/P-gp, at least in part, by targeting HIPk2 in ovarian cancer cells.

Key Molecule: Macrophage colony-stimulating factor 1 (MCSF) [34]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780CIS cells; Ovary; Homo sapiens (Human); CVCL_1942
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Finally downstreamtarget validation was proven for the miR-130a, whose downregulation was linked to the translational activation of the M-CSF gene, a knownresistance factor for ovarian cancer.

Key Molecule: Carboxylesterase 4A (CES4A) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.P55S
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M889K
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.K1655N
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [7]

• Resistant Disease: Ovarian serous carcinoma [ICD-11: 2C73.2]
• Molecule Alteration: Missense mutation; p.K1655N
• Resistant Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [53]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-146a [110]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR146a/SOD2/ROS signaling pathway; Regulation; hsa05206
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; TUNEL Assay
• Mechanism Description: miR146a downregulates the expression of SOD2 and enhances ROS generation, leading to increased apoptosis, inhibition of proliferation, and enhanced sensitivity to chemotherapy.

Key Molecule: hsa-mir-136 [111]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST assay; Spheroid formation assay; Colony-forming assay; TUNEL assay; Wound healing assay
• Mechanism Description: microRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3.

Key Molecule: hsa-miR-383-5p [112]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Hoechst 33
• Mechanism Description: Up-regulation of miR-383-5p inhibited cell proliferation, tumor growth and enhanced chemosensitivity of ovarian cancer cells through suppressing TRIM27 expression.

Key Molecule: hsa-mir-129 [101]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR129/ABCB1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: ABCB1 up-regulated by UCA1/miR-129 axis contributed to PTX resistance in PTX-resistant OC cells.

Key Molecule: hsa-miR-630 [113]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Wound healing assay; Invasion assay; CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-630 inhibitor attenuated chemoresistant epithelial ovarian cancer proliferation and invasion, probably by targeting APAF-1, re-sensitizing the cells to chemotherapy.

Key Molecule: hsa-mir-186 [74]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Both A2780/DDP and A2780/Taxol cells expressed miR-186 at lower levels than A2780. miR-186 overexpression increased the sensitivity of ovarian cancer cell lines to paclitaxel and cisplatin compared with the negative control or mock cells, miR-186 transfection induced cell apoptosis while anti-miR-186 transfection reduced cell apoptosis, suggesting that miR-186 may inhibit the development of drug resistance in ovarian cancer cells. miR-186 overexpression may increase the sensitivity of ovarian cancer cells to paclitaxel by targeting ABCB1 and modulating GST-Pi.

Key Molecule: hsa-miR-133b [53]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Key Molecule: hsa-mir-29b [80]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Key Molecule: hsa-mir-145 [114]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: MCF-7/ADM cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: A2780/PTX cells; Ovary; Homo sapiens (Human); CVCL_IJ13
• In Vitro Model: HOEC cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV3/PTX cells; Ovary; Homo sapiens (Human); CVCL_HF69
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-145 modulates the cellular response to anticancer drugs, Down-regulation of miR-145 is correlated with overexpression of Sp1 and Cdk6, Sp1 and Cdk6 are targets of miR-145, miR-145 downregulated P-gp and pRb through inhibition of Sp1 and Cdk6, miR-145 sensitized EOC cells to paclitaxel via Sp1 and Cdk6 inhibition, Overexpression of miR-145 enhanced paclitaxel sensitivity in vivo.

Key Molecule: hsa-mir-200c [115]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell adhesion; Inhibition; hsa04514
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: OV 1847 cells; Breast; Homo sapiens (Human); CVCL_D703
• In Vitro Model: OVCA 420 cells; Breast; Homo sapiens (Human); CVCL_3935
• In Vivo Model: (NOD) /SCID nude mouse xenograft model; .
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of TUBB3 is thought to result in resistance to taxanes is by enhancement of the dynamic instability of microtubules, thereby counteracting the activity of microtubule targeting agents. Transient restoration of miR-200c using miRNA mimics cause a significant decrease in TUBB3 levels, thus results in the resistance to taxanes.

Key Molecule: hsa-mir-199a [84]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CD44+/CD117+ ovarian CICs cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CD44 plays an important role in cellular adhesion, lymphocyte activation/migration, tumorigenesis, and the formation of metastases, endogenous mature miR-199a may prevent the growth of human ovarian CICs via decreasing the expression of CD44.

Key Molecule: hsa-mir-130b [85]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CSF-1 expression was negatively associated with miR-130b level in ovarian tissues and cell lines. miR-130b modulates MDR by targeting CSF-1, Down-regulation of miR-130b promotes the development of multidrug resistant ovarian cancer partially by targeting the 3'-UTR of CSF-1.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [101]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: UCA1/miR129/ABCB1 signaling pathway; Regulation; hsa05206
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: ABCB1 up-regulated by UCA1/miR-129 axis contributed to PTX resistance in PTX-resistant OC cells.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [74]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Both A2780/DDP and A2780/Taxol cells expressed miR-186 at lower levels than A2780. miR-186 overexpression increased the sensitivity of ovarian cancer cell lines to paclitaxel and cisplatin compared with the negative control or mock cells, miR-186 transfection induced cell apoptosis while anti-miR-186 transfection reduced cell apoptosis, suggesting that miR-186 may inhibit the development of drug resistance in ovarian cancer cells. miR-186 overexpression may increase the sensitivity of ovarian cancer cells to paclitaxel by targeting ABCB1 and modulating GST-Pi.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [53]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-133b increases ovarian cancer cell sensitivity to cisplatin and paclitaxel by decreasing GST-Pi and MDR1 expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Superoxide dismutase Mn (SODM) [110]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR146a/SOD2/ROS signaling pathway; Regulation; hsa05206
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; TUNEL Assay
• Mechanism Description: miR146a downregulates the expression of SOD2 and enhances ROS generation, leading to increased apoptosis, inhibition of proliferation, and enhanced sensitivity to chemotherapy.

Key Molecule: Neurogenic locus notch homolog protein 3 (NOTCH3) [111]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST assay; Spheroid formation assay; Colony-forming assay; TUNEL assay; Wound healing assay
• Mechanism Description: microRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3.

Key Molecule: Zinc finger protein RFP (TRIM27) [112]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: CAOV3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Hoechst 33
• Mechanism Description: Up-regulation of miR-383-5p inhibited cell proliferation, tumor growth and enhanced chemosensitivity of ovarian cancer cells through suppressing TRIM27 expression.

Key Molecule: Apoptotic protease-activating factor 1 (APAF1) [113]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Wound healing assay; Invasion assay; CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-630 inhibitor attenuated chemoresistant epithelial ovarian cancer proliferation and invasion, probably by targeting APAF-1, re-sensitizing the cells to chemotherapy.

Key Molecule: Autophagy-related protein 9A (ATG9A) [80]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Key Molecule: Cyclin-dependent kinase 6 (CDK6) [114]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: MCF-7/ADM cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: A2780/PTX cells; Ovary; Homo sapiens (Human); CVCL_IJ13
• In Vitro Model: HOEC cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV3/PTX cells; Ovary; Homo sapiens (Human); CVCL_HF69
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-145 modulates the cellular response to anticancer drugs, Down-regulation of miR-145 is correlated with overexpression of Sp1 and Cdk6, Sp1 and Cdk6 are targets of miR-145, miR-145 downregulated P-gp and pRb through inhibition of Sp1 and Cdk6, miR-145 sensitized EOC cells to paclitaxel via Sp1 and Cdk6 inhibition, Overexpression of miR-145 enhanced paclitaxel sensitivity in vivo.

Key Molecule: Transcription factor Sp1 (SP1) [114]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: MCF-7/ADM cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: A2780/PTX cells; Ovary; Homo sapiens (Human); CVCL_IJ13
• In Vitro Model: HOEC cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SkOV3/PTX cells; Ovary; Homo sapiens (Human); CVCL_HF69
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-145 modulates the cellular response to anticancer drugs, Down-regulation of miR-145 is correlated with overexpression of Sp1 and Cdk6, Sp1 and Cdk6 are targets of miR-145, miR-145 downregulated P-gp and pRb through inhibition of Sp1 and Cdk6, miR-145 sensitized EOC cells to paclitaxel via Sp1 and Cdk6 inhibition, Overexpression of miR-145 enhanced paclitaxel sensitivity in vivo.

Key Molecule: Tubulin beta-3 chain (TUBB3) [115]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell adhesion; Inhibition; hsa04514
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HEY cells; Ovary; Homo sapiens (Human); CVCL_0297
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCA433 cells; Ovary; Homo sapiens (Human); CVCL_0475
• In Vitro Model: OV 1847 cells; Breast; Homo sapiens (Human); CVCL_D703
• In Vitro Model: OVCA 420 cells; Breast; Homo sapiens (Human); CVCL_3935
• In Vivo Model: (NOD) /SCID nude mouse xenograft model; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of TUBB3 is thought to result in resistance to taxanes is by enhancement of the dynamic instability of microtubules, thereby counteracting the activity of microtubule targeting agents. Transient restoration of miR-200c using miRNA mimics cause a significant decrease in TUBB3 levels, thus results in the resistance to taxanes.

Key Molecule: Extracellular matrix receptor III (CD44) [84]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: CD44+/CD117+ ovarian CICs cells; Ovary; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CD44 plays an important role in cellular adhesion, lymphocyte activation/migration, tumorigenesis, and the formation of metastases, endogenous mature miR-199a may prevent the growth of human ovarian CICs via decreasing the expression of CD44.

Key Molecule: Macrophage colony-stimulating factor 1 (MCSF) [85]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CSF-1 expression was negatively associated with miR-130b level in ovarian tissues and cell lines. miR-130b modulates MDR by targeting CSF-1, Down-regulation of miR-130b promotes the development of multidrug resistant ovarian cancer partially by targeting the 3'-UTR of CSF-1.

Rucaparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [116]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Mutation; .
• Sensitive Drug: Rucaparib
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: Here, we describe HRD mechanisms leading to both platinum and rucaparib sensitivity (BRCA mutation, RAD51C/D alterations, and high BRCA1 promoter methylation) and summarize two important cross-resistance mechanisms: BRCA reversion mutations, and loss of BRCA1 methylation described here for the first time using archival and screening clinical specimens.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Nonsense; p.R1443* (c.4327C>T)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The nonsense p.R1443* (c.4327C>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway.

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Nonsense; p.Q1467* (c.4399C>T)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The nonsense p.Q1467* (c.4399C>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway.

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.C61G (c.181T>G)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.C61G (c.181T>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.C64Y (c.191G>A)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.C64Y (c.191G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M1V (c.1A>G)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.M1V (c.1A>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R71G (c.211A>G)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.R71G (c.211A>G) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R71K (c.212G>A)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.R71K (c.212G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M1I (c.3G>T)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.M1I (c.3G>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R1495M (c.4484G>T)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.R1495M (c.4484G>T) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.E1559K (c.4675G>A)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.E1559K (c.4675G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 1 susceptibility protein (BRCA1) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.D1692N (c.5074G>A)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.D1692N (c.5074G>A) in gene BRCA1 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M1R (c.2T>G)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.M1R (c.2T>G) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M1I (c.3G>T)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.M1I (c.3G>T) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.V159M (c.475G>A)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.V159M (c.475G>A) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.V211L (c.631G>C)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.V211L (c.631G>C) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R2336H (c.7007G>A)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.R2336H (c.7007G>A) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Key Molecule: Breast cancer type 2 susceptibility protein (BRCA2) [117]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R2336P (c.7007G>C)
• Sensitive Drug: Rucaparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• Mechanism Description: The missense mutation p.R2336P (c.7007G>C) in gene BRCA2 cause the sensitivity of Rucaparib by unusual activation of pro-survival pathway

Tamoxifen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-375 [118]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Tamoxifen
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell titer glo assay
• Mechanism Description: Overexpression of MTDH increased mesenchymal markers while downregulating E-cadherin expression, associated with poor prognosis and increased risk of metastasis in breast cancer. Tamoxifen-sensitive cells expressing miRNA-375 at high levels directly represses MTDH expression, and that this regulation confers the cells with a tamoxifen sensitive and epithelial phenotype.

Key Molecule: Protein LYRIC (MTDH) [118]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Tamoxifen
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Cell titer glo assay
• Mechanism Description: Overexpression of MTDH increased mesenchymal markers while downregulating E-cadherin expression, associated with poor prognosis and increased risk of metastasis in breast cancer. Tamoxifen-sensitive cells expressing miRNA-375 at high levels directly represses MTDH expression, and that this regulation confers the cells with a tamoxifen sensitive and epithelial phenotype.

Tirbanibulin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [119]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.G129R (c.385G>A)
• Resistant Drug: Tirbanibulin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: RMUG-S; Ovary; Homo sapiens (Human); CVCL_3158
• In Vitro Model: RMUG-L; Endometrium; Homo sapiens (Human); CVCL_3157
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay; EdU assay; Annexin V and 7-aminoactinomycin D assay; Flow cytometry analysis

Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [120]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: IF-deletion; p.N486_P490delNVTAP (c.1457_1471del15)
• Sensitive Drug: Trametinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Vinblastine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-let-7g [106]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Vinblastine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vitro Model: LOX-IMVI cells; Ovary; Homo sapiens (Human); CVCL_1381
• In Vitro Model: NCI/ADR-RES cells; Ovary; Homo sapiens (Human); CVCL_1452
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: SRB cytotoxicity assay
• Mechanism Description: IMP-1 is an RNA binding protein that acts by stabilizing the mRNA of a number of target genes. In addition, IMP-1 was shown to protect the mRNA of MDR1 from endonucleolytic attack in an in vitro RNA stability assay. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) [106]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vinblastine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• In Vitro Model: LOX-IMVI cells; Ovary; Homo sapiens (Human); CVCL_1381
• In Vitro Model: NCI/ADR-RES cells; Ovary; Homo sapiens (Human); CVCL_1452
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: SRB cytotoxicity assay
• Mechanism Description: IMP-1 is an RNA binding protein that acts by stabilizing the mRNA of a number of target genes. In addition, IMP-1 was shown to protect the mRNA of MDR1 from endonucleolytic attack in an in vitro RNA stability assay. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin.

Clinical Trial Drug(s) 9 drug(s) in total

Camptothecin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-103 [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Camptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: hsa-miR-107 [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Camptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: DNA repair protein RAD51 homolog 1 (RAD51) [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Camptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Key Molecule: DNA repair protein RAD51 homolog 4 (RAD51D) [82]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Camptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: PEO1 C4-2 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Survival assay/crystal violet staining assay
• Mechanism Description: miR-103 and miR-107 reduced homology-directed repair and sensitized cells to various DNA damaging agents, including cisplatin and a PARP inhibitor. Mechanistic analyses revealed that both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D, which is critical for miR-103/107-mediated chemosensitization.

Capivasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [121]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.Q79K (c.235C>A)
• Sensitive Drug: Capivasertib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; .
• Mechanism Description: The missense mutation p.Q79K (c.235C>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [122]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Drug: Capivasertib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing

Ganetespib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [123]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.S241F (c.722C>T)
• Sensitive Drug: Ganetespib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkBR3 cells; Breast; Homo sapiens (Human); CVCL_0033
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-46 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: HOC7 cells; Ascites; Homo sapiens (Human); CVCL_5455
• In Vitro Model: EFO21 cells; Ascites; Homo sapiens (Human); CVCL_0029
• In Vitro Model: COV434 cells; N.A.; Homo sapiens (Human); CVCL_2010
• In Vitro Model: COLO704 cells; Ascites; Homo sapiens (Human); CVCL_1994
• In Vitro Model: HOC7 cells; Ascites; Homo sapiens (Human); CVCL_5455
• In Vivo Model: Athymic (nu/nu) male xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Quantitative PCR analysis
• Experiment for Drug Resistance: CellTiter-blue cell viability assay

Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [124]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: IF-deletion; p.Q56_V60delQKQKV (c.166_180del15)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Whole transcriptome analysis
• Experiment for Drug Resistance: Colony formation assay

Miransertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [125]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Drug: Miransertib
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Miransertib by aberration of the drug's therapeutic target

PF-04691502

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [126]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Drug: PF-04691502
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293-MSR cells; Fetal kidney; Homo sapiens (Human); CVCL_KS18
• In Vivo Model: Female nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Caspase-Glo 3/7 assay
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of PF-04691502 by aberration of the drug's therapeutic target

CH-5132799

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [127]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Drug: CH-5132799
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: KPL-4 cells; Breast; Homo sapiens (Human); CVCL_5310
• In Vitro Model: IGROV1 cells; Ovary; Homo sapiens (Human); CVCL_1304
• In Vitro Model: GXF97 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The missense mutation p.E545K (c.1633G>A) in gene PIK3CA cause the sensitivity of CH-5132799 by aberration of the drug's therapeutic target

Key Molecule: PI3-kinase alpha (PIK3CA) [128]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Drug: CH-5132799
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: ARRAY system assay
• Experiment for Drug Resistance: Presto blue assay

JQ1

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: AT-rich interactive domain-containing protein 1A (ARID1A) [129]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Nonsense; p.Q1148* (c.3442C>T)
• Sensitive Drug: JQ1
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: ES2 cells; Ovary; Homo sapiens (Human); CVCL_AX39
• In Vitro Model: TOV21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: OVCA429 cells; Ovary; Homo sapiens (Human); CVCL_3936
• In Vitro Model: TUOC1 cells; Ovary; Homo sapiens (Human); CVCL_L700
• In Vitro Model: SMOV2 cells; Ovary; Homo sapiens (Human); CVCL_S920
• In Vitro Model: RMGII cells; Ascites; Homo sapiens (Human); CVCL_2803
• In Vitro Model: RMGI cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVAS cells; Ascites; Homo sapiens (Human); CVCL_0V12
• In Vitro Model: OV207 cells; Ovary; Homo sapiens (Human); CVCL_A404
• In Vitro Model: KOC7C cells; Pleural effusion; Homo sapiens (Human); CVCL_5307
• In Vitro Model: HAC2 cells; Ascites; Homo sapiens (Human); CVCL_8354
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The inhibitory effects on residual SWI/SNF function, specifically via reduced ARID1B expression, may explain the enhanced sensitivity of ARID1A mutant cells to BET inhibitors.

LY3009120

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [120]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: IF-deletion; p.N486_P490delNVTAP (c.1457_1471del15)
• Sensitive Drug: LY3009120
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: NIH 3T3 cells; Colon; Homo sapiens (Human); CVCL_0594
• In Vitro Model: HEK 293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: OV-90 cells; Ascites; Homo sapiens (Human); CVCL_3768
• In Vitro Model: H2405 cells; Lung; Homo sapiens (Human); CVCL_1551
• In Vivo Model: NIH nude rat xenograft model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony transformation assay; Cell-cycle analysis; BrdUrd incorporation assay

Preclinical Drug(s) 5 drug(s) in total

A66

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [130]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Drug: A66
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Skin; .
• In Vivo Model: Mouse xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.H1047R (c.3140A>G) in gene PIK3CA cause the sensitivity of A66 by aberration of the drug's therapeutic target

APR-246/Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cellular tumor antigen p53 (TP53) [131]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.L111Q (c.332T>A)
• Sensitive Drug: APR-246/Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ascitic fluid; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FMCA assay

Key Molecule: Cellular tumor antigen p53 (TP53) [131]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.P151H (c.452C>A)
• Sensitive Drug: APR-246/Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ascitic fluid; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FMCA assay

Key Molecule: Cellular tumor antigen p53 (TP53) [131]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.Y163H (c.487T>C)
• Sensitive Drug: APR-246/Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ascitic fluid; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FMCA assay

Key Molecule: Cellular tumor antigen p53 (TP53) [131]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.P278R (c.833C>G)
• Sensitive Drug: APR-246/Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ascitic fluid; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FMCA assay

Key Molecule: Cellular tumor antigen p53 (TP53) [131]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R280K (c.839G>A)
• Sensitive Drug: APR-246/Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ascitic fluid; .
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FMCA assay

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [132]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R248Q (c.743G>A)
• Sensitive Drug: APR-246/Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780-CP20 cells; Ovary; Homo sapiens (Human); CVCL_A5PS
• In Vivo Model: Female CD-1 Nu/Nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: FMCA assay; WST-1 assay; Cell Titer-Glo assay; MTS assay

DS-7423

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [133]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R175H (c.524G>A)
• Resistant Drug: DS-7423
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21 cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: SKOV5 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: RMG-I cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVSAHO cells; Abdomen; Homo sapiens (Human); CVCL_3114
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVKATE cells; Ovary; Homo sapiens (Human); CVCL_3110
• In Vitro Model: OVISE cells; Pelvi; Homo sapiens (Human); CVCL_3116
• In Vitro Model: OV1063 cells; Ascites; Homo sapiens (Human); CVCL_4366
• In Vitro Model: SKOV5 cells; Ovary; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis; Luciferase assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Cellular tumor antigen p53 (TP53) [133]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.S241F (c.722C>T)
• Resistant Drug: DS-7423
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21 cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: SKOV6 cells; Uterus; Homo sapiens (Human); CVCL_A457
• In Vitro Model: RMG-I cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVSAHO cells; Abdomen; Homo sapiens (Human); CVCL_3114
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVKATE cells; Ovary; Homo sapiens (Human); CVCL_3110
• In Vitro Model: OVISE cells; Pelvi; Homo sapiens (Human); CVCL_3116
• In Vitro Model: OV1063 cells; Ascites; Homo sapiens (Human); CVCL_4366
• In Vitro Model: SKOV6 cells; Uterus; Homo sapiens (Human); CVCL_A457
• Experiment for Molecule Alteration: Western blotting analysis; Luciferase assay
• Experiment for Drug Resistance: CCK-8 assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [133]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.C420R (c.1258T>C)
• Sensitive Drug: DS-7423
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: TOV-21 cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: RMG-I cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVSAHO cells; Abdomen; Homo sapiens (Human); CVCL_3114
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVKATE cells; Ovary; Homo sapiens (Human); CVCL_3110
• In Vitro Model: OVISE cells; Pelvi; Homo sapiens (Human); CVCL_3116
• In Vitro Model: OV1063 cells; Ascites; Homo sapiens (Human); CVCL_4366
• Experiment for Molecule Alteration: Western blotting analysis; Luciferase assay
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: PI3-kinase alpha (PIK3CA) [133]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.E545V (c.1634A>T)
• Sensitive Drug: DS-7423
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: TOV-21 cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: SKOV4 cells; Uterus; Homo sapiens (Human); CVCL_X008
• In Vitro Model: RMG-I cells; Ascites; Homo sapiens (Human); CVCL_1662
• In Vitro Model: OVTOKO cells; Spleen; Homo sapiens (Human); CVCL_3117
• In Vitro Model: OVSAHO cells; Abdomen; Homo sapiens (Human); CVCL_3114
• In Vitro Model: OVMANA cells; Ovary; Homo sapiens (Human); CVCL_3111
• In Vitro Model: OVKATE cells; Ovary; Homo sapiens (Human); CVCL_3110
• In Vitro Model: OVISE cells; Pelvi; Homo sapiens (Human); CVCL_3116
• In Vitro Model: OV1063 cells; Ascites; Homo sapiens (Human); CVCL_4366
• In Vitro Model: SKOV4 cells; Uterus; Homo sapiens (Human); CVCL_X008
• Experiment for Molecule Alteration: Western blotting analysis; Luciferase assay
• Experiment for Drug Resistance: CCK-8 assay

NSC319726

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cellular tumor antigen p53 (TP53) [134]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R175H (c.524G>A)
• Sensitive Drug: NSC319726
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: (MEF) (10)3 cells; N.A.; Mus musculus (Mouse); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.R175H (c.524G>A) in gene TP53 cause the sensitivity of NSC319726 by aberration of the drug's therapeutic target

ReACp53

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [135]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.Y327L (c.979_980delTAinsCT)
• Sensitive Drug: ReACp53
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: S1 GODL cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Immunocompromised NSG mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: In vitro 3D organoid assay

Key Molecule: Cellular tumor antigen p53 (TP53) [135]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.R248Q (c.743G>A)
• Sensitive Drug: ReACp53
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: S1 GODL cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Immunocompromised NSG mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: In vitro 3D organoid assay

Key Molecule: Cellular tumor antigen p53 (TP53) [135]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.Y234C (c.701A>G)
• Sensitive Drug: ReACp53
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: S1 GODL cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Immunocompromised NSG mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: In vitro 3D organoid assay

Investigative Drug(s) 9 drug(s) in total

2-hydroxy-5-fluoropyrimidine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [1]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: 2-hydroxy-5-fluoropyrimidine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Anisomycin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Maternally expressed 3 (MEG3) [136]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: Anisomycin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Primary human ovarian cancer stem cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female BALB/c nude mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: Microarray assay; Luciferase assay; Overexpression assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Anisomycin inhibited the activation downstream of the Notch1 pathway by attenuating the molecular sponge effect of the LncRNA Meg3/miR 421/PDGFRA axis, ultimately inhibiting angiogenesis, proliferation and invasion in ovarian cancer cells.

Carboplatin/Liposomal doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Carboxylesterase 4A (CES4A) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.P55S
• Resistant Drug: Carboplatin/Liposomal doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Carboplatin/Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Carboxylesterase 4A (CES4A) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.P55S
• Resistant Drug: Carboplatin/Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

Key Molecule: Mitotic checkpoint serine/threonine-protein kinase BUB1 (BUB1) [7]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M889K
• Resistant Drug: Carboplatin/Paclitaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AXLK signaling pathway; Activation; hsa01521
• In Vitro Model: Plasma; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Circulating-free DNA assay; Whole exome sequencing assay
• Mechanism Description: Quantification of allele fractions in plasma identified increased representation of mutant alleles in association with emergence of therapy resistance.

CI-1040

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [137]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: CI-1040
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: MDA-H2774 cells; Ascites; Homo sapiens (Human); CVCL_0420
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: DAPI assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of CI-1040 by unusual activation of pro-survival pathway

MEK inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: MAPK/ERK kinase 1 (MEK1) [124]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: IF-deletion; p.Q56_V60delQKQKV (c.166_180del15)
• Sensitive Drug: MEK inhibitors
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovary; .
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Whole transcriptome analysis
• Experiment for Drug Resistance: Colony formation assay

Ormaplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 11 (CASC11) [4]

• Resistant Disease: Ovarian squamous cell carcinoma [ICD-11: 2C73.3]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Ormaplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: UWB1.289 cells; Ovary; Homo sapiens (Human); CVCL_B079
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of CASC11 in ovarian squamous cell carcinoma mediates the development of cancer cell resistance to chemotherapy (oxaliplatin, tetraplatin, cisplatin, and carboplatin).

Platinum

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [138]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Platinum
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780_CR5 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: A2780p cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: KURAMOCHI cells; Ovary; Homo sapiens (Human); CVCL_1345
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Caspase 3/7 cleavage assays; Aldefluor assay; MTS assay; Flow cytometric analysis
• Mechanism Description: Blocking the EZH2-interactiing domain of HOTAIR and disrupting the HOTAIR-EZH2 interaction resensitizes cancer cells to clinically relevant cytotoxic chemotherapies, reduces cell invasion and decreases NF-kB transcriptional activity and IL-6 and MMP-9 expression in vivo. Levels of genes like IL6 shown to be up-regulated by HOTAIR.

Key Molecule: hsa-mir-181a [139]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Platinum
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Clonogenicity assay; Cell migration and invasion assay
• Mechanism Description: Smad7 is a direct functional target of miR-181a. There is a striking inverse correlation between miR-181a and Smad7 expression. enhanced miR-181a expression resulted in the activation of other Smad-dependent protein such as TGF-beta R1 and potentially non-canonical TGF-beta-related pathways. By this mechanism the TGF-beta pathway is activated in ovarian cancer tumours and contributes to poor patient outcome.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2) [138]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Platinum
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780_CR5 cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: A2780p cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: KURAMOCHI cells; Ovary; Homo sapiens (Human); CVCL_1345
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblot assay; Western blot analysis
• Experiment for Drug Resistance: Caspase 3/7 cleavage assays; Aldefluor assay; MTS assay; Flow cytometric analysis
• Mechanism Description: Blocking the EZH2-interactiing domain of HOTAIR and disrupting the HOTAIR-EZH2 interaction resensitizes cancer cells to clinically relevant cytotoxic chemotherapies, reduces cell invasion and decreases NF-kB transcriptional activity and IL-6 and MMP-9 expression in vivo.

Key Molecule: Mothers against decapentaplegic homolog 7 (SMAD7) [139]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Platinum
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: TGF-beta signaling pathway; Activation; hsa04350
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Clonogenicity assay; Cell migration and invasion assay
• Mechanism Description: Smad7 is a direct functional target of miR-181a. There is a striking inverse correlation between miR-181a and Smad7 expression. enhanced miR-181a expression resulted in the activation of other Smad-dependent protein such as TGF-beta R1 and potentially non-canonical TGF-beta-related pathways. By this mechanism the TGF-beta pathway is activated in ovarian cancer tumours and contributes to poor patient outcome.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-29b [80]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Platinum
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Autophagy-related protein 9A (ATG9A) [80]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Platinum
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR29b signaling pathway; Regulation; hsa05206
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: H&E staining assay
• Mechanism Description: The ATG9A down expression due to miR-29b increasing could significantly promote Ovarian carcinoma drug sensitivity on different chemotherapeutic drugs (Cisplatin, Paclitaxel, Platinum, Cyclophosphamide).

RAWQ01

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-375 [140]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: RAWQ01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR3 cells; Ovary; Homo sapiens (Human); CVCL_0465
• In Vitro Model: HO8910 cells; Ovary; Homo sapiens (Human); CVCL_6868
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-375 sensitized the ovarian cancer cells to RAWQ01. miR-375 enhanced the in vitro sensitivity of ovarian cancer cells to RAWQ01 by inducing apoptosis. miR-375 also increased the in vivo chemosensitivity of ovarian cancer cells to RAWQ01.

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