Drug Information

Drug (ID: DG00294) and It's Reported Resistant Information

• Name: Carboplatin
• Synonyms: Azanide; Carbopaltin; Carboplatine; Carboplatino; Carboplatinum; Cbdca; Ercar; Paraplatin; Carboplatine [French]; Carboplatino [Spanish]; Carboplatinum [Latin]; C 2538; JM 8; Carboplatin (USAN); IUPAC: Azane; JM-8; Paraplatin (TN); Paraplatin, Carboplatin; Paraplatin-AQ; Cis-Diammine(cyclobutanedicarboxylato)platinumII; Platinum(+2) Cation; Carboplatin (JAN/USP/INN); Carboplatin [USAN:INN:BAN:JAN]; Cyclobutane-1,1-dicarboxylate; Cyclobutane-1,1-dicarboxylic acid; Diammine-1,1-cyclobutane dicarboxylate platinum II; Cis-Diamine[1,1-cyclobutanedicarboxylato]platinum(II); Cis-Diammine(1,1-cyclobutanedicarboxylato) platinum; Cis-Diammine(1,1-cyclobutanedicarboxylato)platinum; Cis-Diammine[1,1-cyclobutane-dicarboxylato] platinum; Diammine(1,1-cyclobutanedicarboxylato)platinum (II); Platinum, {diammine[1,1-cyclobut; Cis-(1,1-Cyclobutanedicarboxylato)diammineplatinum(II); Cis-Diamine(1,1-cyclobutanedicarboxylato)platinum(II); Cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II); Platinum(II), (1, 1-cyclobutanedicar; Diammine[cyclobutane-1,1-dicarboxylato(2-)-k2O1,O1]platinum; Diammine(cyclobutane-1,1-dicarboxylato(2-)-O,O')platinum; Platinum, diammine(1,1-cyclobutanedicarboxylato(2-)-O,O')-, (SP-4-2); (SP-4-2)-diammine[cyclobutane-1,1-dicarboxylato(2-)-kappa(2)O,O']platinum; 1,1-Cyclobutanedicarboxylate diammine platinum (II); 1,1-Cyclobutanedicarboxylate diammine platinum(II)
• Indication:
  In total 1 Indication(s)
  Ovarian cancer [ICD-11: 2C73]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (6 diseases)
  Epithelial ovarian cancer [ICD-11: 2B5D]; [2]
  Esophageal cancer [ICD-11: 2B70]; [8]
  Liver cancer [ICD-11: 2C12]; [9]
  Osteosarcoma [ICD-11: 2B51]; [10]
  Ovarian cancer [ICD-11: 2C73]; [11]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [12]
  Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
  Fallopian tube cancer [ICD-11: 2C74]; [3]
  Merkel cell carcinoma [ICD-11: 2C34]; [5]
  Ovarian cancer [ICD-11: 2C73]; [6]
  Pituitary cancer [ICD-11: 2F37]; [7]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Lung cancer [ICD-11: 2C25]; [4]
• Target: Human Deoxyribonucleic acid (hDNA); NOUNIPROTAC; [1]
• Formula: C6H12N2O4Pt
• IsoSMILES: C1CC(C1)(C(=O)O)C(=O)O.[NH2-].[NH2-].[Pt+2]
• InChI: 1S/C6H8O4.2H2N.Pt/c7-4(8)6(5(9)10)2-1-3-6;;;/h1-3H2,(H,7,8)(H,9,10);2*1H2;/q;2*-1;+2
• InChIKey: VSRXQHXAPYXROS-UHFFFAOYSA-N
• PubChem CID: 426756
• ChEBI ID: CHEBI:31355
• TTD Drug ID: D0X7HM
• DrugBank ID: DB00958

Type(s) of Resistant Mechanism of This Drug

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  MRAP: Metabolic Reprogramming via Altered Pathways

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Ovarian cancer [ICD-11: 2C73]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Metalloproteinase inhibitor 1 (TIMP1) [13]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.62E-21; Fold-change: 5.18E-01; Z-score: 1.09E+01
• 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: hsa-miR-34c-5p [19]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• 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 [20]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• 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) [13]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• 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) [13]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• 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.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Amphiregulin (AREG) [19]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• 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) [20]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• 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) [20]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• 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) [20]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• 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) [20]

• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Regulation; N.A.
• 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.

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin-8 (IL8) [3]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.91E-02; Fold-change: 2.94E-01; Z-score: 1.93E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• 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: Cysteine-rich motor neuron 1 protein (CRIM1) [11]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Ovarian cancer [ICD-11: 2C73]
• The Specified Disease: Ovarian cancer
• The Studied Tissue: Ovarian tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.22E-05; Fold-change: -1.29E-01; Z-score: -7.42E+00
• 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) [11]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• 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) [6]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.P55S
• 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) [6]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Missense mutation; p.M889K
• 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) [3]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• 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) [3]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• 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) [3]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ovarian cancer tissue; N.A.
• 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: Fibroblast growth factor 2 (FGF1) [18]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: A2780DPP cells; Ovary; Homo sapiens (Human); N.A.
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: Caov-3 cells; Ovary; Homo sapiens (Human); CVCL_0201
• Experiment for Molecule Alteration: qRT-PCR; Immunoblotting assay
• Experiment for Drug Resistance: MTT assay; In vitro chemosensitivity assay
• Mechanism Description: Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance.FGF receptor inhibition re-sensitises cells to cisplatin and carboplatin. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7027 re-sensitised resistant cells.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 11 (CASC11) [1]

• Resistant Disease: Ovarian squamous cell carcinoma [ICD-11: 2C73.3]
• Molecule Alteration: Expression; Up-regulation
• 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 [11]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• 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.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: OTU deubiquitinase, ubiquitin aldehyde binding 2 (OTUB2) [16]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: Functional experiments using both transgenic mouse models and human cancer-derived models confirmed the critical tumor-suppressive role of OTUB2 in ovarian cancer. Intriguingly, we identified sorting nexin 29 pseudogene 2 (SNX29P2), an ill-defined protein with biased expression in ovarian tissue, as a bona fide substrate of OTUB2. The deubiquitination and stabilization of SNX29P2 by OTUB2 promotes the interaction between the E3 ligase VHL and HIF-1alpha and results in HIF-1alpha degradation, consequently inhibiting the expression of CA9. Activation of CA9 restores OTUB2-mediated inhibition of glycolysis and tumor growth; thus, CA9 inhibitors might be a promising strategy for ovarian cancer treatment.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-141 [17]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• 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 [17]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Down-regulation
• 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) [17]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Molecule Alteration: Expression; Up-regulation
• 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.

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: TP53 target 1 (TP53TG1) [12]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: GCIY cells; Gastric; Homo sapiens (Human); CVCL_1228
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: MkN-7 cells; Gastric; Homo sapiens (Human); CVCL_1417
• In Vitro Model: SNU-1 cells; Gastric; Homo sapiens (Human); CVCL_0099
• In Vitro Model: TGBC11TkB cells; Gastric; Homo sapiens (Human); CVCL_1768
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
• Mechanism Description: TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Y-box-binding protein 1 (YBX1) [12]

• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• In Vitro Model: GCIY cells; Gastric; Homo sapiens (Human); CVCL_1228
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: MkN-7 cells; Gastric; Homo sapiens (Human); CVCL_1417
• In Vitro Model: SNU-1 cells; Gastric; Homo sapiens (Human); CVCL_0099
• In Vitro Model: TGBC11TkB cells; Gastric; Homo sapiens (Human); CVCL_1768
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; TUNEL assay; xCELLigence Real-Time invasion and migration assays
• Mechanism Description: TP53TG1, a p53-induced LncRNA, binds to the multifaceted RNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. The epigenetic silencing of TP53TG1 in cancer cells promotes the YBX1-mediated activation of the PI3k/AkT pathway, which then creates further resistance not only to common chemotherapy RNA-damaging agents but also to small drug-targeted inhibitors.

Osteosarcoma [ICD-11: 2B51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34a-5p [14]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
• Mechanism Description: The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene.

Key Molecule: hsa-miR-199a-3p [15]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.

Key Molecule: hsa-miR-34a-5p [10]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Up-regulation
• 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: MEF2 signaling pathway; Regulation; N.A.
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Type-1 angiotensin II receptor (AGTR1) [14]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC/propidium iodide (PI) staining assay
• Mechanism Description: The miR34a-5p promotes the multi-chemoresistance of osteosarcoma via repression of the AGTR1 gene.

Key Molecule: Adenylate kinase 4 (AK4) [15]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The Ak4 gene is one of the targets of miR-199a-3p and negatively correlates with the effect of miR-199a-3p on OS drug-resistance.

Key Molecule: Mast/stem cell growth factor receptor Kit (KIT) [10]

• Resistant Disease: Osteosarcoma [ICD-11: 2B51.0]
• Molecule Alteration: Expression; Down-regulation
• 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: MEF2 signaling pathway; Regulation; N.A.
• In Vitro Model: MG63 cells; Bone marrow; Homo sapiens (Human); CVCL_0426
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: U2OS cells; Bone; Homo sapiens (Human); CVCL_0042
• In Vitro Model: G-292 cells; Bone; Homo sapiens (Human); CVCL_2909
• In Vitro Model: SJSA-1 cells; Bone; Homo sapiens (Human); CVCL_1697
• In Vitro Model: MG63.2 cells; Bone; Homo sapiens (Human); CVCL_R705
• In Vitro Model: MNNG/HOS cells; Bone; Homo sapiens (Human); CVCL_0439
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The down-regulation of CD117 mediated by miR-34a-5p might be one of the reasons for OS drug resistance. CD117 may also regulate other processes, including cell adhesion, differentiation and migration, which are significant for cancer development and treatment.

Epithelial ovarian cancer [ICD-11: 2B5D]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Molecule Alteration: Phosphorylation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR-3 cells; Ascites; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• Mechanism Description: We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFkappaB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [2]

• Resistant Disease: Epithelial ovarian cancer [ICD-11: 2B5D.0]
• Molecule Alteration: Phosphorylation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SKOV-3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: OVCAR-3 cells; Ascites; Homo sapiens (Human); CVCL_0465
• In Vitro Model: OVCAR5 cells; Ovary; Homo sapiens (Human); CVCL_1628
• In Vitro Model: OVCAR8 cells; Ovary; Homo sapiens (Human); CVCL_1629
• Mechanism Description: We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFkappaB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1.

Esophageal cancer [ICD-11: 2B70]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Copper-transporting ATPase 1 (ATP7A) [8]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: EC109 cells; Esophagus; Homo sapiens (Human); CVCL_6898
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of ATP7A in EC109/cisplatin cells might increase pumping platinum out of cells or binding and sequestration of platinum drugs, then decrease cellular platinum concentration or keep them away from accessing their key cytotoxic targets in the nucleus, finally result in cisplatin-resistance.

Liver cancer [ICD-11: 2C12]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-146a [9]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-miR-146b-5p [9]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181a [9]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-181d [9]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Key Molecule: hsa-mir-27b [9]

• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The HCC Huh-7 cell line was treated with adramycin (ADM), cisplatin (DDP), carboplatin (CBP), mitomycin C (MMC) or vincristine (VCR) at increasing concentrations to develop drug-resistant sublines. Among these 51 upregulated and downregulated miRNAs, 12 miRNAs were upregulated and 13 miRNAs were downregulated in Huh-7/VCR. Upregulation of miR-27b, miR-181a, miR-146b-5p, miR-181d and miR-146a expression was verified using real-time RT-PCR in the parental and the five drug-resistant cell lines.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Aldo-keto reductase family 1 member B10 (AKR1B10) [4]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: MU375/MU383 patient-derived tumor organoids; Homo sapiens
• Experiment for Molecule Alteration: qPCR; IHC assay
• Experiment for Drug Resistance: Drug sensitivity testing
• Mechanism Description: Epalrestat can be repurposed to overcome chemoresistance. PDTOs retained histomorphology and pathological biomarker expression, mutational/transcriptomic signatures, and cellular heterogeneity of the matched tumor tissues. Five (50%) PDTOs were chemoresistant toward carboplatin/paclitaxel. Chemoresistant PDTOs and matched tumor tissues demonstrated overexpression of AKR1B10. Epalrestat, an orally available AKR1B10 inhibitor in clinical use for diabetic polyneuropathy, was repurposed to overcome chemoresistance of PDTOs. In vivo efficacy of epalrestat to overcome drug resistance corresponded to intratumoral epalrestat levels.

Merkel cell carcinoma [ICD-11: 2C34]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [5]

• Resistant Disease: Merkel cell carcinoma [ICD-11: 2C34.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MKL-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_D027
• In Vitro Model: WaGa cells; Ascites; Homo sapiens (Human); CVCL_E998
• In Vitro Model: MKL-1 cells; Liver; Homo sapiens (Human); CVCL_2600
• In Vitro Model: MS-1 cells; Lung; Homo sapiens (Human); CVCL_IQ55
• In Vivo Model: NSG mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: These findings in patient specimens were consistent with the possibility that ABCB5+ MCC cells are preferentially resistant to treatment with the first-line chemotherapeutic agents, carboplatin and etoposide.

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [5]

• Resistant Disease: Merkel cell carcinoma [ICD-11: 2C34.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MKL-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_D027
• In Vitro Model: WaGa cells; Ascites; Homo sapiens (Human); CVCL_E998
• In Vitro Model: MKL-1 cells; Liver; Homo sapiens (Human); CVCL_2600
• In Vitro Model: MS-1 cells; Lung; Homo sapiens (Human); CVCL_IQ55
• In Vivo Model: NSG mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: These findings in patient specimens were consistent with the possibility that ABCB5+ MCC cells are preferentially resistant to treatment with the first-line chemotherapeutic agents, carboplatin and etoposide.

Fallopian tube cancer [ICD-11: 2C74]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin 6 receptor (IL6R) [3]

• Resistant Disease: Fallopian tube cancer [ICD-11: 2C74.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Fallopian tube cancer tissue; N.A.
• 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) [3]

• Resistant Disease: Fallopian tube cancer [ICD-11: 2C74.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Fallopian tube cancer tissue; N.A.
• 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.

Retina cancer [ICD-11: 2D02]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [21]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAGE-A/p53 signaling pathway; Regulation; N.A.
• In Vitro Model: HXO-Rb44 cells; Retina; Homo sapiens (Human); CVCL_D542
• In Vitro Model: SO-Rb50 cells; Retina; Homo sapiens (Human); CVCL_D543
• In Vitro Model: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vitro Model: Y79 cells; Retina; Homo sapiens (Human); CVCL_1893
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Freedom Evolyzer-2200 Enzyme-Linked Immunometric meter; Flow cytometry assay
• Mechanism Description: miR-34a may function as a tumor suppressor for RB by targeting MAGE-A and upregulating p53 expression to enhance cell apoptosis and chemosensitivity (Carboplatin; Etoposide; Adriamycin; vincristine).

Key Molecule: hsa-miR-3163 [22]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Molecule Alteration: Expression; Up-regulation
• 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: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [22]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Molecule Alteration: Expression; Down-regulation
• 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: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Silencing of ABCG2 by MicroRNA-3163 inhibits multidrug resistance in retinoblastoma cancer stem cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Melanoma antigen A 4 (MAGE4) [21]

• Sensitive Disease: Retinoblastoma [ICD-11: 2D02.2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAGE-A/p53 signaling pathway; Regulation; N.A.
• In Vitro Model: HXO-Rb44 cells; Retina; Homo sapiens (Human); CVCL_D542
• In Vitro Model: SO-Rb50 cells; Retina; Homo sapiens (Human); CVCL_D543
• In Vitro Model: WERI-Rb-1 cells; Retina; Homo sapiens (Human); CVCL_1792
• In Vitro Model: Y79 cells; Retina; Homo sapiens (Human); CVCL_1893
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Freedom Evolyzer-2200 Enzyme-Linked Immunometric meter; Flow cytometry assay
• Mechanism Description: miR-34a may function as a tumor suppressor for RB by targeting MAGE-A and upregulating p53 expression to enhance cell apoptosis and chemosensitivity (Carboplatin; Etoposide; Adriamycin; vincristine).

Pituitary cancer [ICD-11: 2F37]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [7]

• Resistant Disease: Pituitary adenoma [ICD-11: 2F37.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pituitary tumour stem-like cells; Pituitary; Homo sapiens (Human); N.A.
• In Vivo Model: NOD/SCID mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Stem cells are generally known to preferentially express antiapoptotic genes, such as BCL-2, cIAP1, NAIP, and XIAP.The expression levels of these antiapoptotic genes in PASC1 were one- to sixfolds higher than those in its daughter cells.

Key Molecule: Baculoviral IAP repeat containing 2 (BIRC2) [7]

• Resistant Disease: Pituitary adenoma [ICD-11: 2F37.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pituitary tumour stem-like cells; Pituitary; Homo sapiens (Human); N.A.
• In Vivo Model: NOD/SCID mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Stem cells are generally known to preferentially express antiapoptotic genes, such as BCL-2, cIAP1, NAIP, and XIAP.The expression levels of these antiapoptotic genes in PASC1 were one- to sixfolds higher than those in its daughter cells.

Key Molecule: Baculoviral IAP repeat-containing protein 1 (BIRC1) [7]

• Resistant Disease: Pituitary adenoma [ICD-11: 2F37.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pituitary tumour stem-like cells; Pituitary; Homo sapiens (Human); N.A.
• In Vivo Model: NOD/SCID mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Stem cells are generally known to preferentially express antiapoptotic genes, such as BCL-2, cIAP1, NAIP, and XIAP.The expression levels of these antiapoptotic genes in PASC1 were one- to sixfolds higher than those in its daughter cells.

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [7]

• Resistant Disease: Pituitary adenoma [ICD-11: 2F37.1]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pituitary tumour stem-like cells; Pituitary; Homo sapiens (Human); N.A.
• In Vivo Model: NOD/SCID mice xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 proliferation assay
• Mechanism Description: Stem cells are generally known to preferentially express antiapoptotic genes, such as BCL-2, cIAP1, NAIP, and XIAP.The expression levels of these antiapoptotic genes in PASC1 were one- to sixfolds higher than those in its daughter cells.

References

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