Disease Information

General Information of the Disease (ID: DIS00099)

• Name: Bladder cancer
• ICD: ICD-11: 2C94

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) 14 drug(s) in total

Cetuximab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-200b [1]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cetuximab
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: 253J BV cells; Bladder; Homo sapiens (Human); CVCL_7937
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Pulse-labeling cells with [3H]thymidine
• Mechanism Description: Members of the miR-200 family appear to control the EMT process and sensitivity to EGFR therapy, in bladder cancer cells and that expression of miR-200 is sufficient to restore EGFR dependency, at least in some of the mesenchymal bladder cancer cells. The targets of miR-200 include ERRFI-1, which is a novel regulator of EGFR-independent growth.

Key Molecule: hsa-mir-200c [1]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cetuximab
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: 253J BV cells; Bladder; Homo sapiens (Human); CVCL_7937
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Pulse-labeling cells with [3H]thymidine
• Mechanism Description: Members of the miR-200 family appear to control the EMT process and sensitivity to EGFR therapy, in bladder cancer cells and that expression of miR-200 is sufficient to restore EGFR dependency, at least in some of the mesenchymal bladder cancer cells. The targets of miR-200 include ERRFI-1, which is a novel regulator of EGFR-independent growth.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: ERBB receptor feedback inhibitor 1 (ERRFI1) [1]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cetuximab
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Regulation; hsa01521
• In Vitro Model: 253J BV cells; Bladder; Homo sapiens (Human); CVCL_7937
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Pulse-labeling cells with [3H]thymidine
• Mechanism Description: Members of the miR-200 family appear to control the EMT process and sensitivity to EGFR therapy, in bladder cancer cells and that expression of miR-200 is sufficient to restore EGFR dependency, at least in some of the mesenchymal bladder cancer cells. The targets of miR-200 include ERRFI-1, which is a novel regulator of EGFR-independent growth.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34b-3p [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p represses the multidrug-chemoresistance (Paclitaxel; Pirarubicin; Epirubicin hydrochloride; Adriamycin; Cisplatin) of bladder cancer cells by regulating the CCND2 and P2RY1 genes.

Key Molecule: hsa-mir-98 [3]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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 proliferation; Activation; hsa05200
• Cell Pathway Regulation: Drp1 signaling pathway; Activation; hsa04668
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: microRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells through Drp1 signaling.

Key Molecule: HIF1A antisense RNA 3 (HIF1A-AS3) [4]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Upregulated HIF1A-AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer.

Key Molecule: hsa-miR-196a-5p [5]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR196a-5p in bladder cancer cells. UCA1 upregulates miR196a-5p through transcription factor CREB.

Key Molecule: hsa-miR-22-3p [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Key Molecule: Urothelial cancer associated 1 (UCA1) [7]

• Resistant Disease: Urinary bladder cancer [ICD-11: 2C94.Z]
• 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 viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin-based chemotherapy results in up-regulation of UCA1 expression, UCA1 increases cell viability during cisplatin treatment, UCA1 activates Wnt signaling in a Wnt6-dependent manner, UCA1 promotes cisplatin resistance by up-regulating Wnt6 expression.

Key Molecule: Long non-protein coding RNA (UCA1a) [8]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: Cell viability; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vitro Model: BLZ-211 cells; Bladder; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Moreover, microarray analysis demonstrated that overexpression of UCA1a(CUDR) was associated with signaling pathways regulating cell apoptosis and tumorigen-esis. Furthermore, overexpression of UCA1a(CUDR) could antagonize cell apoptosis induced by cisplatin and promote the tumorigenicity of UM-UC-2 cells in vivo.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [9]

• Resistant Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The expression levels of miR34a were decreased and GOLPH3 were increased in GC chemoresistant UBC cell lines. Down-regulation of miR34a resulted in the overexpression of GOLPH3.The ectopic expression of miR34a decreased the stem cell properties of chemoresistant UBC cells and re-sensitized these cells to GC treatment in vitro and in vivo.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Interleukin-1 beta (IL1B) [10]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vivo Model: Balb/cA Jcl nu/nu nude mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Cell count assay
• Mechanism Description: Aldo-keto reductase 1C1 (AkR1C1), plays an essential role in cancer invasion/metastasis and chemoresistance. Antagonized AkR1C1 and decreased the cisplatin-resistance and invasion potential of metastatic sublines. Metastatic tumor cells possess higher expression levels of endogenous IL-6 and IL-1beta and their receptors. IL-1beta enhanced the expression of AkR1C1 in the three bladder cancer cell lines, UM-UC-3, TCC-SUP, and 5637 cells. Inhibition of 17beta-estradiol by AkR1C1 may recover cell motility in cancer cells.

Key Molecule: Transcription factor SOX-2 (SOX2) [11]

• Resistant Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: BFTC 909 cells; Kidney; Homo sapiens (Human); CVCL_1084
• In Vitro Model: BFTC 905 cells; Urinary bladder; Homo sapiens (Human); CVCL_1083
• In Vitro Model: HT-1376 cells; Urinary bladder; Homo sapiens (Human); CVCL_1292
• In Vitro Model: SCaBER cells; Urinary bladder; Homo sapiens (Human); CVCL_3599
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: UM-UC3 cells; Urinary bladder; Homo sapiens (Human); CVCL_1783
• In Vivo Model: Athymic (nu+/nu+) mouse xenograft model; NOD/SCID/IL2Rgamma -/- mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Mechanism Description: Chemotherapy-induced COX2 and YAP1 signaling may promote CSC expansion via SOX2 overexpression and subsequent chemotherapy resistance.The YAP1-SOX2 axis, via re-activated PI3K/AKT signaling, may also be relevant to an acquired resistance to the EGFR inhibitor, as demonstrated by our findings that the resistant tumors again became sensitive to the EGFR inhibitor in combination with the YAP1 inhibitor.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D2 (CCND2) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p represses the multidrug-chemoresistance (Paclitaxel; Pirarubicin; Epirubicin hydrochloride; Adriamycin; Cisplatin) of bladder cancer cells by regulating the CCND2 and P2RY1 genes.

Key Molecule: P2Y purinoceptor 1 (P2RY1) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p represses the multidrug-chemoresistance (Paclitaxel; Pirarubicin; Epirubicin hydrochloride; Adriamycin; Cisplatin) of bladder cancer cells by regulating the CCND2 and P2RY1 genes.

Key Molecule: Ceramide synthase 2 (CERS2) [3]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Drp1 signaling pathway; Activation; hsa04668
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: microRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells through Drp1 signaling.

Key Molecule: High mobility group protein HMG-I/HMG-Y (HMGA1) [4]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: HMGA1 contributes to Cis resistance in bladder cancer by hampering the transcription activity of p53 family proteins.

Key Molecule: Cellular tumor antigen p53 (TP53) [4]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Upregulated HIF1A-AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer.

Key Molecule: Apoptosis regulator BAX (BAX) [4]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Upregulated HIF1A-AS2 hampers the p53 family proteins dependent apoptotic pathway to promote Cis resistance in bladder cancer.

Key Molecule: Cyclin-dependent kinase inhibitor 1B (CDKN1B) [5]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: miR196a-5p is involved in UCA1-mediated cisplatin/gemcitabine resistance via targeting p27kip1.

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Key Molecule: Protein Wnt-6 (WNT6) [7]

• Resistant Disease: Urinary bladder cancer [ICD-11: 2C94.Z]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt signaling pathway; Activation; hsa04310
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin-based chemotherapy results in up-regulation of UCA1 expression, UCA1 increases cell viability during cisplatin treatment, UCA1 activates Wnt signaling in a Wnt6-dependent manner, UCA1 promotes cisplatin resistance by up-regulating Wnt6 expression.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-214 [12]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT phosphorylation signaling pathway; Inhibition; hsa00190
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 214 reduces chemoresistance by targeting netrin 1 in bladder cancer cell lines and inhibits AkT phosphorylation.

Key Molecule: hsa-mir-218 [13]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR218-Glut1 signaling pathway; Regulation; hsa05206
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR218 increases the sensitivity of bladder cancer to cisplatin by targeting Glut1.

Key Molecule: Urothelial cancer associated 1 (UCA1) [5]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR196a-5p in bladder cancer cells. UCA1 upregulates miR196a-5p through transcription factor CREB.

Key Molecule: hsa-miR-1182 [14]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: BCa cells; Bladder; Homo sapiens (Human); N.A.
• In Vitro Model: Hcv29 cells; Bladder; Homo sapiens (Human); CVCL_8228
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-1182 was significantly downregulated in bladder cancer cells and tumor tissues. miR-1182 inhibited cell proliferation and invasion, induced apoptosis and cell cycle arrest, and mediated the chemosensitivity of bladder cancer cells to cisplatin by targeting hTERT.

Key Molecule: hsa-mir-203 [15]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-203 could directly bind the 3'-UTR of both Bcl-w and Survivin, resulting in down-regulated expression of Bcl-w and Survivin at post-transcriptional level. miR-203 can be used as a predictor for progression and prognosis of BC patients treated with cisplatin based chemotherapy. Moreover, overexpression of miR-203 can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

Key Molecule: hsa-miR-193a-3p [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Key Molecule: hsa-mir-150 [17]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-150 functions as a tumor promoter in reducing chemosensitivity and promoting invasiveness of MIBC cells via downretulating PDCD4.

Key Molecule: hsa-mir-101 [18]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by downregulating the cyclooxygenase-2 pathway.

Key Molecule: hsa-mir-27a [19]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: EJ/T24 cells; Bladder; Homo sapiens (Human); N.A.
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Clonogenic survival assay
• Mechanism Description: Cisplatin resistance is mediated through increased expression of SLC7A11 and increased production of glutathione, Overexpression of microRNA 27a reduces levels of SLC7A11 and intracellular glutathione, and resensitises resistant cells to cisplatin, SLC7A11 is a key modulator of cisplatin resistance in bladder cancer cells.

Key Molecule: hsa-mir-34 [20]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Tumorigenicity in nude mice
• Mechanism Description: Cisplatin-based chemotherapy induced demethylation of miR-34a promoter and increased miR-34a expression, which in turn sensitized MIBC cells to cisplatin and decreased the tumorigenicity and proliferation of cancer cells that by reducing the production of CD44.

Key Molecule: hsa-mir-34 [21]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Cdk6, in complex with Cdk4 and cyclin D1, is a key regulator of Rb activity and thereby G1/S transition, SIRT-1 is a deacetylase whose targets including p53, FOXO, SFRP1 and PGC1. Transfection with pre-miR-34a increases chemo-sensitivity to cisplatin through inhibition of Cdk6 and SIRT-1.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Solute carrier family 2 member 1 (SLC2A1) [13]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR218-Glut1 signaling pathway; Regulation; hsa05206
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR218 increases the sensitivity of bladder cancer to cisplatin by targeting Glut1.

Key Molecule: Cystine/glutamate transporter (SLC7A11) [19]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: EJ/T24 cells; Bladder; Homo sapiens (Human); N.A.
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• Experiment for Molecule Alteration: Tissue array assay
• Experiment for Drug Resistance: Clonogenic survival assay
• Mechanism Description: Cisplatin resistance is mediated through increased expression of SLC7A11 and increased production of glutathione, Overexpression of microRNA 27a reduces levels of SLC7A11 and intracellular glutathione, and resensitises resistant cells to cisplatin, SLC7A11 is a key modulator of cisplatin resistance in bladder cancer cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Netrin-1 (NTN1) [12]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT phosphorylation signaling pathway; Inhibition; hsa00190
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 214 reduces chemoresistance by targeting netrin 1 in bladder cancer cell lines and inhibits AkT phosphorylation.

Key Molecule: Telomerase reverse transcriptase (TERT) [14]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: BCa cells; Bladder; Homo sapiens (Human); N.A.
• In Vitro Model: Hcv29 cells; Bladder; Homo sapiens (Human); CVCL_8228
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-1182 was significantly downregulated in bladder cancer cells and tumor tissues. miR-1182 inhibited cell proliferation and invasion, induced apoptosis and cell cycle arrest, and mediated the chemosensitivity of bladder cancer cells to cisplatin by targeting hTERT.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [15]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-203 could directly bind the 3'-UTR of both Bcl-w and Survivin, resulting in down-regulated expression of Bcl-w and Survivin at post-transcriptional level. miR-203 can be used as a predictor for progression and prognosis of BC patients treated with cisplatin based chemotherapy. Moreover, overexpression of miR-203 can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [15]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-203 could directly bind the 3'-UTR of both Bcl-w and Survivin, resulting in down-regulated expression of Bcl-w and Survivin at post-transcriptional level. miR-203 can be used as a predictor for progression and prognosis of BC patients treated with cisplatin based chemotherapy. Moreover, overexpression of miR-203 can enhance cisplatin sensitization by promoting apoptosis via directly targeting Bcl-w and Survivin.

Key Molecule: Presenilin-1 (PSEN1) [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Key Molecule: Programmed cell death protein 4 (PDCD4) [17]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-150 functions as a tumor promoter in reducing chemosensitivity and promoting invasiveness of MIBC cells via downretulating PDCD4.

Key Molecule: Prostaglandin G/H synthase 2 (PTGS2) [18]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by downregulating the cyclooxygenase-2 pathway.

Key Molecule: Extracellular matrix receptor III (CD44) [20]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Tumorigenicity in nude mice
• Mechanism Description: Cisplatin-based chemotherapy induced demethylation of miR-34a promoter and increased miR-34a expression, which in turn sensitized MIBC cells to cisplatin and decreased the tumorigenicity and proliferation of cancer cells that by reducing the production of CD44.

Key Molecule: Cyclin-dependent kinase 6 (CDK6) [21]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Cdk6, in complex with Cdk4 and cyclin D1, is a key regulator of Rb activity and thereby G1/S transition, SIRT-1 is a deacetylase whose targets including p53, FOXO, SFRP1 and PGC1. Transfection with pre-miR-34a increases chemo-sensitivity to cisplatin through inhibition of Cdk6 and SIRT-1.

Key Molecule: NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [21]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: Cdk6, in complex with Cdk4 and cyclin D1, is a key regulator of Rb activity and thereby G1/S transition, SIRT-1 is a deacetylase whose targets including p53, FOXO, SFRP1 and PGC1. Transfection with pre-miR-34a increases chemo-sensitivity to cisplatin through inhibition of Cdk6 and SIRT-1.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34b-3p [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: hsa-mir-98 [3]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Drp1 signaling pathway; Activation; hsa04668
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: microRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells through Drp1 signaling.

Key Molecule: Growth arrest specific 5 (GAS5) [22]

• Resistant Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: T24/DOX cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Dual-color flow cytometric method; Annexin V-FITC apoptosis assay
• Mechanism Description: Long noncoding RNA GAS5 inhibits malignant proliferation and chemotherapy resistance to doxorubicin in bladder transitional cell carcinoma.

Key Molecule: hsa-miR-22-3p [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Key Molecule: hsa-mir-21 [23]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• 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: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: A negative correlation between expression of miR-21 and pten was established in vivo. cell proliferation and chemoresistance to doxorubicin were promoted by overexpression of miR-21 in t24 cells. Bcl-2 up-regulation could be achieved by miR-21 overexpression, which prevented t24 cells from apoptosis induced by doxorubicin.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [24]

• Resistant Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Non-coding RNA NEAT1/miR-214-3p contribute to doxorubicin resistance of urothelial bladder cancer preliminary through the Wnt/beta-catenin pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D2 (CCND2) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: P2Y purinoceptor 1 (P2RY1) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: Ceramide synthase 2 (CERS2) [3]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Drp1 signaling pathway; Activation; hsa04668
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: microRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells through Drp1 signaling.

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

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

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• 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: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: A negative correlation between expression of miR-21 and pten was established in vivo. cell proliferation and chemoresistance to doxorubicin were promoted by overexpression of miR-21 in t24 cells. Bcl-2 up-regulation could be achieved by miR-21 overexpression, which prevented t24 cells from apoptosis induced by doxorubicin.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-193a-3p [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [25]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: Cell viability; Inhibition; hsa05200
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: CT26 cells; Colon; Mus musculus (Mouse); CVCL_7254
• In Vitro Model: Salmonella enterica serovar Typhimurium SL1344; 216597
• In Vitro Model: Salmonella enterica serovar Typhimurium SL1344 detaSipA; 216597
• In Vitro Model: Salmonella enterica serovar Typhimurium SL1344 detaSipB; 216597
• In Vitro Model: Salmonella enterica serovar Typhimurium SL1344 detaSipC; 216597
• In Vitro Model: Salmonella enterica serovar Typhimurium SL1344 detaSopB; 216597
• In Vivo Model: BALB/c nude mice xenograft model; Mus musculus
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Presenilin-1 (PSEN1) [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Epirubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34b-3p [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Epirubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: hsa-miR-22-3p [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Epirubicin
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D2 (CCND2) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Epirubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: P2Y purinoceptor 1 (P2RY1) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Epirubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Epirubicin
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [26]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Epirubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis.

Key Molecule: hsa-miR-193a-3p [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Epirubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Lymphoid enhancer-binding factor 1 (LEF1) [26]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Epirubicin
• 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 invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis.

Key Molecule: Transcription factor 7 (TCF7) [26]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Epirubicin
• 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 invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Regulation; hsa04310
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34a increased chemosensitivity in BIU87/ADR cells by inhibiting the TCF1/LEF1 axis.

Key Molecule: Presenilin-1 (PSEN1) [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Epirubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Erdafitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G370C (c.1108G>T)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.R248C (c.742C>T)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S371C (c.1111A>T)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G380R (c.1138G>A)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Synonymous; p.K650K (c.1950G>A)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G370C (c.1108G>T)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.R248C (c.742C>T)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [27]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: Erdafitinib
• Experimental Note: Identified from the Human Clinical Data

Erlotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: ERBB receptor feedback inhibitor 1 (ERRFI1) [29]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Erlotinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200a [29]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Erlotinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200b [29]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Erlotinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Key Molecule: hsa-mir-200c [29]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Erlotinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-Beta/miR200/MIG6 signaling pathway; Inhibition; hsa05206
• In Vitro Model: Calu3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: H292 cells; Lung; Homo sapiens (Human); CVCL_0455
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: NCI-H358 cells; Lung; Homo sapiens (Human); CVCL_1559
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: H1703 cells; Lung; Homo sapiens (Human); CVCL_1490
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: Calu6 cells; Lung; Homo sapiens (Human); CVCL_0236
• In Vitro Model: H1838 cells; Lung; Homo sapiens (Human); CVCL_1499
• In Vitro Model: H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; RT-PCR
• Experiment for Drug Resistance: Alamar Blue assay
• Mechanism Description: The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFbeta-induced EMT-associated kinase switch of tumor cells to an AkT-activated state, thereby leading to an EGFR-independent phenotype that is refractory to EGFR TkI. the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Moreover, analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio is inversely correlated with response to erlotinib in vivo.

Gemcitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-196a-5p [5]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR196a-5p in bladder cancer cells. UCA1 upregulates miR196a-5p through transcription factor CREB.

Key Molecule: hsa-miR-22-3p [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [9]

• Resistant Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The expression levels of miR34a were decreased and GOLPH3 were increased in GC chemoresistant UBC cell lines. Down-regulation of miR34a resulted in the overexpression of GOLPH3.The ectopic expression of miR34a decreased the stem cell properties of chemoresistant UBC cells and re-sensitized these cells to GC treatment in vitro and in vivo.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Transcription factor SOX-2 (SOX2) [11]

• Resistant Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: BFTC 909 cells; Kidney; Homo sapiens (Human); CVCL_1084
• In Vitro Model: BFTC 905 cells; Urinary bladder; Homo sapiens (Human); CVCL_1083
• In Vitro Model: HT-1376 cells; Urinary bladder; Homo sapiens (Human); CVCL_1292
• In Vitro Model: SCaBER cells; Urinary bladder; Homo sapiens (Human); CVCL_3599
• In Vitro Model: RT-4 cells; Urinary bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: UM-UC3 cells; Urinary bladder; Homo sapiens (Human); CVCL_1783
• In Vivo Model: Athymic (nu+/nu+) mouse xenograft model; NOD/SCID/IL2Rgamma -/- mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting assay
• Mechanism Description: Chemotherapy-induced COX2 and YAP1 signaling may promote CSC expansion via SOX2 overexpression and subsequent chemotherapy resistance.The YAP1-SOX2 axis, via re-activated PI3K/AKT signaling, may also be relevant to an acquired resistance to the EGFR inhibitor, as demonstrated by our findings that the resistant tumors again became sensitive to the EGFR inhibitor in combination with the YAP1 inhibitor.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cyclin-dependent kinase inhibitor 1B (CDKN1B) [5]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Gemcitabine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: miR196a-5p is involved in UCA1-mediated cisplatin/gemcitabine resistance via targeting p27kip1.

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Gemcitabine
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-143 [30]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R signaling pathway; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK sigaling pathway; Inhibition; hsahsa04
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR143 inhibits bladder cancer cell proliferation and enhances their sensitivity to gemcitabine by repressing IGF-1R signaling. Down-regulation of miR143 in bladder cancer may be involved in tumor development via the activation of IGF-1R and other downstream pathways like PI3k/Akt and MAPk.

Key Molecule: Urothelial cancer associated 1 (UCA1) [5]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: UMUC-2 cells; Bladder; Homo sapiens (Human); CVCL_8155
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR196a-5p in bladder cancer cells. UCA1 upregulates miR196a-5p through transcription factor CREB.

Key Molecule: hsa-miR-129-5p [31]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• 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: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-129-5p inhibits gemcitabine resistance and promotes cell apoptosis of bladder cancer cells by downregulating Wnt5a.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [30]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: IGF1R signaling pathway; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK sigaling pathway; Inhibition; hsahsa04
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR143 inhibits bladder cancer cell proliferation and enhances their sensitivity to gemcitabine by repressing IGF-1R signaling. Down-regulation of miR143 in bladder cancer may be involved in tumor development via the activation of IGF-1R and other downstream pathways like PI3k/Akt and MAPk.

Key Molecule: Protein Wnt-5a (WNT5A) [31]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gemcitabine
• 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: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-129-5p inhibits gemcitabine resistance and promotes cell apoptosis of bladder cancer cells by downregulating Wnt5a.

Glutathione

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [32]

• Resistant Disease: Bladder carcinoma [ICD-11: 2C94.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Glutathione
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: SABC immunohistochemistry assay
• Mechanism Description: In the 119 cases of bladder carcinoma, the positive rate of HIF-1alpha was 57.9%, the positive rate of GST-Pi was 67.2%. Co-expression of HIF-1alpha and GST-Pi is a object index for judging differentiation and chemoresistance of bladder cancer. GTS-Pi catalyzes the combination of glutathione and drugs to form gh-x, which makes it easier to excrete cells and cause drug resistance of cancer.

Infigratinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G370C (c.1108G>T)
• Sensitive Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.R248C (c.742C>T)
• Sensitive Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S371C (c.1111A>T)
• Sensitive Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G380R (c.1138G>A)
• Sensitive Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Synonymous; p.K650K (c.1950G>A)
• Sensitive Drug: Infigratinib
• Experimental Note: Identified from the Human Clinical Data

Mitomycin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-31 [34]

• Sensitive Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Mitomycin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Regulation; hsa04010
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-31 expression brings about (+) sensitivity of UBC to MMC by suppressing ITGA5 and downstream pathways.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Integrin alpha-5 (ITGA5) [34]

• Sensitive Disease: Bladder urothelial carcinoma [ICD-11: 2C94.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Mitomycin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Regulation; hsa04010
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-31 expression brings about (+) sensitivity of UBC to MMC by suppressing ITGA5 and downstream pathways.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34b-3p [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: hsa-miR-22-3p [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Key Molecule: hsa-miR-193a-3p [35], [36], [37]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: DNA damage repair signaling pathway; Inhibition; hsa03410
• Cell Pathway Regulation: DNA damage response/Oxidative stress signaling pathway; Inhibition; hsa04218
• Cell Pathway Regulation: Myc/Max signaling pathway; Inhibition; hsa04218
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• Cell Pathway Regulation: Notch signaling pathway; Activation; hsa04330
• Cell Pathway Regulation: Oxidative stress signaling pathway; Regulation; hsa00190
• Cell Pathway Regulation: Oxidative stress signaling pathway; Activation; hsa00190
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• 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-193a-3p promotes the BCa multi-drug resistance phenotype via its repression of the lysyl oxidase-like 4 (LOXL4) gene, a newly identified direct target of miR-193a-3p. The LOXL4 protein is an important member of the lysyl oxidase (an extracellular copper-dependent amine oxidase) family that catalyzes the first step of the crosslinks between collagens and elastin during the biogenesis of connective tissue and is frequently deregulated in cancer. The Oxidative stress (OS) pathway is the predominant pathway affected by miR-193a-3p via its repression of LOXL4 expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D2 (CCND2) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: P2Y purinoceptor 1 (P2RY1) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Key Molecule: Homeobox protein Hox-C9 (HOXC9) [37]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: DNA damage response/Oxidative stress signaling pathway; Inhibition; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-193a-3p promotes the multi-chemoresistance of bladder cancer by targeting the HOXC9 gene.

Key Molecule: Lysyl oxidase homolog 4 (LOXL4) [36]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: Oxidative stress signaling pathway; Regulation; hsa00190
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-193a-3p promotes the BCa multi-drug resistance phenotype via its repression of the lysyl oxidase-like 4 (LOXL4) gene, a newly identified direct target of miR-193a-3p. The LOXL4 protein is an important member of the lysyl oxidase (an extracellular copper-dependent amine oxidase) family that catalyzes the first step of the crosslinks between collagens and elastin during the biogenesis of connective tissue and is frequently deregulated in cancer. The Oxidative stress (OS) pathway is the predominant pathway affected by miR-193a-3p via its repression of LOXL4 expression.

Key Molecule: Hypermethylated in cancer 2 protein (HIC2) [35]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA damage repair signaling pathway; Inhibition; hsa03410
• Cell Pathway Regulation: Myc/Max signaling pathway; Inhibition; hsa04218
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• Cell Pathway Regulation: Notch signaling pathway; Activation; hsa04330
• Cell Pathway Regulation: Oxidative stress signaling pathway; Activation; hsa00190
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression.

Key Molecule: Urokinase-type plasminogen activator (PLAU) [35]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA damage repair signaling pathway; Inhibition; hsa03410
• Cell Pathway Regulation: Myc/Max signaling pathway; Inhibition; hsa04218
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• Cell Pathway Regulation: Notch signaling pathway; Activation; hsa04330
• Cell Pathway Regulation: Oxidative stress signaling pathway; Activation; hsa00190
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression.

Key Molecule: Serine/arginine-rich splicing factor 2 (SRSF2) [35]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA damage repair signaling pathway; Inhibition; hsa03410
• Cell Pathway Regulation: Myc/Max signaling pathway; Inhibition; hsa04218
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• Cell Pathway Regulation: Notch signaling pathway; Activation; hsa04330
• Cell Pathway Regulation: Oxidative stress signaling pathway; Activation; hsa00190
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: BIU87 cells; Bladder; Homo sapiens (Human); CVCL_6881
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-193a-3p [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Presenilin-1 (PSEN1) [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• 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: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Pirarubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-34b-3p [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: hsa-miR-22-3p [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pirarubicin
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: G1/S-specific cyclin-D2 (CCND2) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: P2Y purinoceptor 1 (P2RY1) [2]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch/PkC/Ca++ signaling pathway; Inhibition; hsa04330
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• 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
• Mechanism Description: miR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes.

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Pirarubicin
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-193a-3p [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Presenilin-1 (PSEN1) [16]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Pirarubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: DNA damage response signaling pathway; Activation; hsa04218
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Among the differentially expressed genes between the chemosensitive (5637) and chemoresistant (H-bc) bladder cancer cell lines, the expression level of the PSEN1 gene (presenilin 1), a key component of the Gamma-secretase, is negatively correlated with chemoresistance. A small interfering RNA mediated repression of the PSEN1 gene suppresses cell apoptosis and de-sensitizes 5637 cells, while overexpression of the presenilin 1 sensitizes H-bc cells to the drug-triggered cell death. As a direct target of microRNA-193a-3p that promotes the multi-chemoresistance of the bladder cancer cell, PSEN1 acts as an important executor for the microRNA-193a-3p's positive impact on the multi-chemoresistance of bladder cancer, probably via its activating effect on DNA damage response pathway. In addition to the mechanistic insights, the key players in this microRNA-193a-3p/PSEN1 axis are likely the diagnostic and/or therapeutic targets for an effective chemotherapy of bladder cancer.

Sirolimus

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-582-5p [38]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Sirolimus
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: UCA1 knockdown suppresses growth, migration, and invasion of T24 and 5637 cells via derepression of miR-582-5p and ATG7 was downregulated by UCA1 shRNA and upregulated by miR-582-5p inhibitor.

Key Molecule: Urothelial cancer associated 1 (UCA1) [38]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sirolimus
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: UCA1 knockdown suppresses growth, migration, and invasion of T24 and 5637 cells via derepression of miR-582-5p and ATG7 was downregulated by UCA1 shRNA and upregulated by miR-582-5p inhibitor.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [38]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sirolimus
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: EJ cells; Bladder; Homo sapiens (Human); CVCL_UI82
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: SV-HUC-1 cells; Bladder; Homo sapiens (Human); CVCL_3798
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• 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: UCA1 knockdown suppresses growth, migration, and invasion of T24 and 5637 cells via derepression of miR-582-5p and ATG7 was downregulated by UCA1 shRNA and upregulated by miR-582-5p inhibitor.

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) [39]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Other; .
• Sensitive Drug: Trametinib
• Experimental Note: Identified from the Human Clinical Data

Clinical Trial Drug(s) 8 drug(s) in total

Cediranib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [40]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.Y375C (c.1124A>G)
• Resistant Drug: Cediranib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.Y375C (c.1124A>G) in gene FGFR3 cause the resistance of Cediranib by unusual activation of pro-survival pathway

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [40]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: Cediranib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.S249C (c.746C>G) in gene FGFR3 cause the sensitivity of Cediranib by unusual activation of pro-survival pathway

Derazantinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [41]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.K652E (c.1954A>G)
• Sensitive Drug: Derazantinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: A2780 cells; Ovary; Homo sapiens (Human); CVCL_0134
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SNU-16 cells; Gastric; Homo sapiens (Human); CVCL_0076
• In Vitro Model: AN3CA cells; Ovary; Homo sapiens (Human); CVCL_0028
• In Vitro Model: SkOV3 cells; Ovary; Homo sapiens (Human); CVCL_0532
• In Vitro Model: K562 cells; Blood; Homo sapiens (Human); CVCL_0004
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: RT-112 cells; Urinary bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: MFM-223 cells; Pleural effusion; Homo sapiens (Human); CVCL_1408
• In Vitro Model: MFE296 cells; Endometrium; Homo sapiens (Human); CVCL_1406
• In Vitro Model: MFE280 cells; Endometrium; Homo sapiens (Human); CVCL_1405
• In Vitro Model: COS-1 cells; Kidney; Chlorocebus aethiops (Green monkey); CVCL_0223
• In Vivo Model: SCID beige mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2alpha, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions.

Selumetinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [42]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S310F (c.929C>T)
• Resistant Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vitro Model: UM-UC3 cells; Urinary bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: WH cells; Bladder; Homo sapiens (Human); CVCL_0C39
• In Vitro Model: VM-CUBIII cells; Urinary bladder; Homo sapiens (Human); CVCL_9830
• In Vitro Model: VM-CUBII cells; Urinary bladder; Homo sapiens (Human); CVCL_9829
• In Vitro Model: VM-CUBI cells; Obturator lymph node; Homo sapiens (Human); CVCL_1786
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: TSU-PR1 cells; Urinary bladder; Homo sapiens (Human); CVCL_4014
• In Vitro Model: SW1710 cells; Bladder; Homo sapiens (Human); CVCL_1721
• In Vitro Model: SD cells; Bladder; Homo sapiens (Human); CVCL_W902
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: JO'N cells; Urinary bladder; Homo sapiens (Human); CVCL_M891
• In Vitro Model: JMSU-1 cells; Ascites; Homo sapiens (Human); CVCL_2081
• In Vitro Model: HT1197 cells; Urinary bladder; Homo sapiens (Human); CVCL_1291
• In Vitro Model: DSH1 cells; Urinary bladder; Homo sapiens (Human); CVCL_1182
• In Vitro Model: CAL-29 cells; Urinary bladder; Homo sapiens (Human); CVCL_1808
• In Vitro Model: BFTC-905 cells; Urinary bladder; Homo sapiens (Human); CVCL_1083
• In Vitro Model: BC-3C cells; Urinary bladder; Homo sapiens (Human); CVCL_1958
• In Vitro Model: 97-7 cells; Bladder; Homo sapiens (Human); CVCL_8625
• In Vitro Model: 97-24 cells; Bladder; Homo sapiens (Human); CVCL_8621
• In Vitro Model: 97-18 cells; Bladder; Homo sapiens (Human); CVCL_8619
• In Vitro Model: 97-1 cells; Bladder; Homo sapiens (Human); CVCL_8616
• In Vitro Model: 96-1 cells; Bladder; Homo sapiens (Human); CVCL_8609
• In Vitro Model: 94-10 cells; Bladder; Homo sapiens (Human); CVCL_8608
• In Vitro Model: 647V cells; Urinary bladder; Homo sapiens (Human); CVCL_1049
• In Vitro Model: 253J cells; Lymph node; Homo sapiens (Human); CVCL_7935/CVCL_7938
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

Key Molecule: Receptor tyrosine-protein kinase erbB-2 (ERBB2) [42]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S653C (c.1958C>G)
• Resistant Drug: Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: SW780 cells; Bladder; Homo sapiens (Human); CVCL_1728
• In Vitro Model: HT1376 cells; Bladder; Homo sapiens (Human); CVCL_1292
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vitro Model: UM-UC3 cells; Urinary bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: WH cells; Bladder; Homo sapiens (Human); CVCL_0C39
• In Vitro Model: VM-CUBIII cells; Urinary bladder; Homo sapiens (Human); CVCL_9830
• In Vitro Model: VM-CUBII cells; Urinary bladder; Homo sapiens (Human); CVCL_9829
• In Vitro Model: VM-CUBI cells; Obturator lymph node; Homo sapiens (Human); CVCL_1786
• In Vitro Model: UM-UC-14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: TSU-PR1 cells; Urinary bladder; Homo sapiens (Human); CVCL_4014
• In Vitro Model: SW1710 cells; Bladder; Homo sapiens (Human); CVCL_1721
• In Vitro Model: SD cells; Bladder; Homo sapiens (Human); CVCL_W902
• In Vitro Model: KU-19 cells; Blood; Bos taurus (Bovine); CVCL_VN09
• In Vitro Model: JO'N cells; Urinary bladder; Homo sapiens (Human); CVCL_M891
• In Vitro Model: JMSU-1 cells; Ascites; Homo sapiens (Human); CVCL_2081
• In Vitro Model: HT1197 cells; Urinary bladder; Homo sapiens (Human); CVCL_1291
• In Vitro Model: DSH1 cells; Urinary bladder; Homo sapiens (Human); CVCL_1182
• In Vitro Model: CAL-29 cells; Urinary bladder; Homo sapiens (Human); CVCL_1808
• In Vitro Model: BFTC-905 cells; Urinary bladder; Homo sapiens (Human); CVCL_1083
• In Vitro Model: BC-3C cells; Urinary bladder; Homo sapiens (Human); CVCL_1958
• In Vitro Model: 97-7 cells; Bladder; Homo sapiens (Human); CVCL_8625
• In Vitro Model: 97-24 cells; Bladder; Homo sapiens (Human); CVCL_8621
• In Vitro Model: 97-18 cells; Bladder; Homo sapiens (Human); CVCL_8619
• In Vitro Model: 97-1 cells; Bladder; Homo sapiens (Human); CVCL_8616
• In Vitro Model: 96-1 cells; Bladder; Homo sapiens (Human); CVCL_8609
• In Vitro Model: 94-10 cells; Bladder; Homo sapiens (Human); CVCL_8608
• In Vitro Model: 647V cells; Urinary bladder; Homo sapiens (Human); CVCL_1049
• In Vitro Model: 253J cells; Lymph node; Homo sapiens (Human); CVCL_7935/CVCL_7938
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay

AZD-4547

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: AZD-4547
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Synonymous; p.K650K (c.1950G>A)
• Sensitive Drug: AZD-4547
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G370C (c.1108G>T)
• Sensitive Drug: AZD-4547
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Drug: AZD-4547
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.R248C (c.742C>T)
• Sensitive Drug: AZD-4547
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S371C (c.1111A>T)
• Sensitive Drug: AZD-4547
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G380R (c.1138G>A)
• Sensitive Drug: AZD-4547
• Experimental Note: Identified from the Human Clinical Data

DEBIO-1347

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [43]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Synonymous; p.K650K (c.1950G>A)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G370C (c.1108G>T)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.R248C (c.742C>T)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S371C (c.1111A>T)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [28]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G380R (c.1138G>A)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [33]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data

Hydroxycamptothecin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-22-3p [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Hydroxycamptothecin
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neuroepithelial cell-transforming gene 1 protein (NET1) [6]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Hydroxycamptothecin
• 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: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• In Vitro Model: H-bc cells; Bladder; Homo sapiens (Human); CVCL_BT00
• In Vitro Model: HTB-1 cells; Bladder; Homo sapiens (Human); CVCL_0359
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells.

Pictilisib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [44]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.D549Y (c.1645G>T)
• Resistant Drug: Pictilisib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Activation; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

Key Molecule: Phosphatase and tensin homolog (PTEN) [44]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.N48I (c.143A>T)
• Resistant Drug: Pictilisib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Activation; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

Trichostatin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [45]

• Resistant Disease: Bladder carcinoma [ICD-11: 2C94.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Key Molecule: hsa-miR-199a-5p [45]

• Resistant Disease: Bladder carcinoma [ICD-11: 2C94.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Key Molecule: hsa-mir-30d [45]

• Resistant Disease: Bladder carcinoma [ICD-11: 2C94.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: BGC-823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• In Vitro Model: MGC-803 cells; Gastric; Homo sapiens (Human); CVCL_5334
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• In Vitro Model: MkN-45 cells; Gastric; Homo sapiens (Human); CVCL_0434
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Endoplasmic reticulum chaperone BiP (HSPA5) [45]

• Resistant Disease: Bladder carcinoma [ICD-11: 2C94.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Preclinical Drug(s) 6 drug(s) in total

Binimetinib/Everolimus

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Hras (HRAS) [46]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• Sensitive Drug: Binimetinib/Everolimus
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: RL952 cells; Endometrium; Homo sapiens (Human); CVCL_0505
• In Vitro Model: NCI-H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vitro Model: KYSE-30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: KNS62 cells; Brain; Homo sapiens (Human); CVCL_1335
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: HCC44 cells; Lung; Homo sapiens (Human); CVCL_2060
• In Vitro Model: CAL-12T cells; Lung; Homo sapiens (Human); CVCL_1105
• In Vivo Model: CB17 SCID-/- mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

Cisplatin/Pictilisib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [44]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Drug: Cisplatin/Pictilisib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

Everolimus/Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Hras (HRAS) [46]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• Sensitive Drug: Everolimus/Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: RL952 cells; Endometrium; Homo sapiens (Human); CVCL_0505
• In Vitro Model: NCI-H1915 cells; Lung; Homo sapiens (Human); CVCL_1505
• In Vitro Model: KYSE-30 cells; Esophagus; Homo sapiens (Human); CVCL_1351
• In Vitro Model: KNS62 cells; Brain; Homo sapiens (Human); CVCL_1335
• In Vitro Model: HCC78 cells; Pleural effusion; Homo sapiens (Human); CVCL_2061
• In Vitro Model: HCC44 cells; Lung; Homo sapiens (Human); CVCL_2060
• In Vitro Model: CAL-12T cells; Lung; Homo sapiens (Human); CVCL_1105
• In Vivo Model: CB17 SCID-/- mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay

NS1

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Hras (HRAS) [47]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.Q61L (c.182A>T)
• Sensitive Drug: NS1
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ras signaling pathway; Inhibition; hsa04014
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: NIH3T3 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: COS cells; N.A.; .; N.A.
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: NS1, that bound with high affinity to both GTP- and GDP-bound states of H- and K-RAS but not N-RAS. NS1 potently inhibited growth factor signaling and oncogenic H- and K-RAS-mediated signaling and transformation but did not block oncogenic N-RAS, BRAF or MEK1. NS1 bound the alpha4-beta6-alpha5 region of RAS disrupting RAS dimerization/nanoclustering, which in turn blocked CRAF:BRAF heterodimerization and activation. These results establish the importance of the alpha4-beta6-alpha5 interface in RAS-mediated signaling and define a previously unrecognized site in RAS for inhibiting RAS function.

Pictilisib/Sorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [44]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Drug: Pictilisib/Sorafenib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MEK/ERK signaling pathway; Inhibition; hsa04011
• In Vitro Model: 5637 cells; Bladder; Homo sapiens (Human); CVCL_0126
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• In Vitro Model: TCCSuP cells; Bladder; Homo sapiens (Human); CVCL_1738
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Drug Resistance: MTS assay; FACS assay
• Mechanism Description: Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance.

R3Mab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [48]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: R3Mab
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: RT4 cells; Bladder; Homo sapiens (Human); CVCL_0036
• In Vitro Model: KMS11 cells; Peripheral blood; Homo sapiens (Human); CVCL_2989
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: UTMC-2 cells; Pleural effusion; Homo sapiens (Human); CVCL_4802
• In Vitro Model: TCC-97-7 cells; Bladder; Homo sapiens (Human); CVCL_8625
• In Vitro Model: TCC-97-7 cells; Bladder; Homo sapiens (Human); CVCL_8625
• In Vitro Model: OPM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vivo Model: Female nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Mechanism Description: The missense mutation p.S249C (c.746C>G) in gene FGFR3 cause the sensitivity of R3Mab by aberration of the drug's therapeutic target

Investigative Drug(s) 1 drug(s) in total

FGFR inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor (FGFR) [49]

• Resistant Disease: Bladder cancer [ICD-11: 2C94.0]
• Molecule Alteration: Mutation; .
• Resistant Drug: FGFR inhibitors
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK/MAPKsignaling pathway; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• In Vitro Model: 639V cells; Bladder; Homo sapiens (Human); CVCL_1048
• In Vitro Model: MGHU3 cells; Bladder; Homo sapiens (Human); CVCL_9827
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Screening assay
• Mechanism Description: In particular, epidermal growth factor receptor (EGFR) activation has been identified as a mechanism of resistance in bladder cancer cells with FGFR3 mutations after treatment with FGFR inhibitors.

References

• Ref 1: miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clin Cancer Res. 2009 Aug 15;15(16):5060-72. doi: 10.1158/1078-0432.CCR-08-2245. Epub 2009 Aug 11.
• Ref 2: MiR-34b-3p Represses the Multidrug-Chemoresistance of Bladder Cancer Cells by Regulating the CCND2 and P2RY1 Genes. Med Sci Monit. 2019 Feb 19;25:1323-1335. doi: 10.12659/MSM.913746.
• Ref 3: MicroRNA-98 promotes drug resistance and regulates mitochondrial dynamics by targeting LASS2 in bladder cancer cells. Exp Cell Res. 2018 Dec 15;373(1-2):188-197. doi: 10.1016/j.yexcr.2018.10.013. Epub 2018 Oct 25.
• Ref 4: The long noncoding RNA HIF1A-AS2 facilitates cisplatin resistance in bladder cancer. J Cell Biochem. 2019 Jan;120(1):243-252. doi: 10.1002/jcb.27327. Epub 2018 Sep 14.
• Ref 5: Long non-coding RNA UCA1 promotes cisplatin/gemcitabine resistance through CREB modulating miR-196a-5p in bladder cancer cells. Cancer Lett. 2016 Nov 1;382(1):64-76. doi: 10.1016/j.canlet.2016.08.015. Epub 2016 Aug 31.
• Ref 6: miR 22 3p enhances multi chemoresistance by targeting NET1 in bladder cancer cells. Oncol Rep. 2018 Jun;39(6):2731-2740. doi: 10.3892/or.2018.6355. Epub 2018 Apr 4.
• Ref 7: Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. FEBS J. 2014 Apr;281(7):1750-8. doi: 10.1111/febs.12737. Epub 2014 Feb 20.
• Ref 8: Long non-coding RNA UCA1a(CUDR) promotes proliferation and tumorigenesis of bladder cancer. Int J Oncol. 2012 Jul;41(1):276-84. doi: 10.3892/ijo.2012.1443. Epub 2012 Apr 20.
• Ref 9: miR34a/GOLPH3 Axis abrogates Urothelial Bladder Cancer Chemoresistance via Reduced Cancer Stemness .Theranostics. 2017 Oct 17;7(19):4777-4790. doi: 10.7150/thno.21713. eCollection 2017. 10.7150/thno.21713
• Ref 10: Aldo-keto reductase 1C1 induced by interleukin-1Beta mediates the invasive potential and drug resistance of metastatic bladder cancer cells. Sci Rep. 2016 Oct 4;6:34625. doi: 10.1038/srep34625.
• Ref 11: YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells .Cancer Res. 2018 Jan 1;78(1):168-181. doi: 10.1158/0008-5472.CAN-17-0836. Epub 2017 Nov 27. 10.1158/0008-5472.CAN-17-0836
• Ref 12: miR 214 reduces cisplatin resistance by targeting netrin 1 in bladder cancer cells. Int J Mol Med. 2018 Mar;41(3):1765-1773. doi: 10.3892/ijmm.2018.3374. Epub 2018 Jan 10.
• Ref 13: MicroRNA-218 Increases the Sensitivity of Bladder Cancer to Cisplatin by Targeting Glut1. Cell Physiol Biochem. 2017;41(3):921-932. doi: 10.1159/000460505. Epub 2017 Feb 20.
• Ref 14: miR-1182 inhibits growth and mediates the chemosensitivity of bladder cancer by targeting hTERT. Biochem Biophys Res Commun. 2016 Feb 5;470(2):445-452. doi: 10.1016/j.bbrc.2016.01.014. Epub 2016 Jan 7.
• Ref 15: MicroRNA-203 Is a Prognostic Indicator in Bladder Cancer and Enhances Chemosensitivity to Cisplatin via Apoptosis by Targeting Bcl-w and Survivin. PLoS One. 2015 Nov 23;10(11):e0143441. doi: 10.1371/journal.pone.0143441. eCollection 2015.
• Ref 16: The miR-193a-3p regulated PSEN1 gene suppresses the multi-chemoresistance of bladder cancer. Biochim Biophys Acta. 2015 Mar;1852(3):520-8. doi: 10.1016/j.bbadis.2014.12.014. Epub 2014 Dec 24.
• Ref 17: miR-150 modulates cisplatin chemosensitivity and invasiveness of muscle-invasive bladder cancer cells via targeting PDCD4 in vitro. Med Sci Monit. 2014 Oct 7;20:1850-7. doi: 10.12659/MSM.891340.
• Ref 18: Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by modulating the cyclooxygenase-2 pathway. Mol Med Rep. 2014 Oct;10(4):2203-9. doi: 10.3892/mmr.2014.2455. Epub 2014 Aug 6.
• Ref 19: Reduced expression of miRNA-27a modulates cisplatin resistance in bladder cancer by targeting the cystine/glutamate exchanger SLC7A11. Clin Cancer Res. 2014 Apr 1;20(7):1990-2000. doi: 10.1158/1078-0432.CCR-13-2805. Epub 2014 Feb 10.
• Ref 20: Cisplatin-induced epigenetic activation of miR-34a sensitizes bladder cancer cells to chemotherapy. Mol Cancer. 2014 Jan 15;13:8. doi: 10.1186/1476-4598-13-8.
• Ref 21: MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status. Int J Cancer. 2012 Jun 1;130(11):2526-38. doi: 10.1002/ijc.26256. Epub 2011 Dec 2.
• Ref 22: Long noncoding RNA GAS5 inhibits malignant proliferation and chemotherapy resistance to doxorubicin in bladder transitional cell carcinoma. Cancer Chemother Pharmacol. 2017 Jan;79(1):49-55. doi: 10.1007/s00280-016-3194-4. Epub 2016 Nov 22.
• Ref 23: microRNA-21 modulates cell proliferation and sensitivity to doxorubicin in bladder cancer cells. Oncol Rep. 2011 Jun;25(6):1721-9. doi: 10.3892/or.2011.1245. Epub 2011 Apr 4.
• Ref 24: Non-coding RNA NEAT1/miR-214-3p contribute to doxorubicin resistance of urothelial bladder cancer preliminary through the Wnt/Beta-catenin pathway .Cancer Manag Res. 2018 Oct 11;10:4371-4380. doi: 10.2147/CMAR.S171126. eCollection 2018. 10.2147/CMAR.S171126
• Ref 25: A Salmonella nanoparticle mimic overcomes multidrug resistance in tumours. Nat Commun. 2016 Jul 25;7:12225. doi: 10.1038/ncomms12225.
• Ref 26: MicroRNA-34a Attenuates Metastasis and Chemoresistance of Bladder Cancer Cells by Targeting the TCF1/LEF1 Axis. Cell Physiol Biochem. 2018;48(1):87-98. doi: 10.1159/000491665. Epub 2018 Jul 12.
• Ref 27: Erdafitinib in Locally Advanced or Metastatic Urothelial CarcinomaN Engl J Med. 2019 Jul 25;381(4):338-348. doi: 10.1056/NEJMoa1817323.
• Ref 28: Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivoBr J Cancer. 2011 Jan 4;104(1):75-82. doi: 10.1038/sj.bjc.6606016. Epub 2010 Nov 30.
• Ref 29: The TGFBeta-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. Cancer Res. 2014 Jul 15;74(14):3995-4005. doi: 10.1158/0008-5472.CAN-14-0110. Epub 2014 May 15.
• Ref 30: miR-143 inhibits bladder cancer cell proliferation and enhances their sensitivity to gemcitabine by repressing IGF-1R signaling. Oncol Lett. 2017 Jan;13(1):435-440. doi: 10.3892/ol.2016.5388. Epub 2016 Nov 16.
• Ref 31: miR-129-5p inhibits gemcitabine resistance and promotes cell apoptosis of bladder cancer cells by targeting Wnt5a. Int Urol Nephrol. 2018 Oct;50(10):1811-1819. doi: 10.1007/s11255-018-1959-x. Epub 2018 Aug 16.
• Ref 32: [Expression and significance of GST-Pi and HIF-1alpha in bladder carcinoma]. Ai Zheng. 2006 Feb;25(2):190-3.
• Ref 33: A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene AlterationsClin Cancer Res. 2019 May 1;25(9):2699-2707. doi: 10.1158/1078-0432.CCR-18-1959. Epub 2019 Feb 11.
• Ref 34: MicroRNA-31 functions as a tumor suppressor and increases sensitivity to mitomycin-C in urothelial bladder cancer by targeting integrin Alpha5. Oncotarget. 2016 May 10;7(19):27445-57. doi: 10.18632/oncotarget.8479.
• Ref 35: The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression. Cell Death Dis. 2014 Sep 4;5(9):e1402. doi: 10.1038/cddis.2014.367.
• Ref 36: miR-193a-3p regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene and the oxidative stress pathway. Mol Cancer. 2014 Oct 14;13:234. doi: 10.1186/1476-4598-13-234.
• Ref 37: MiR-193a-3p promotes the multi-chemoresistance of bladder cancer by targeting the HOXC9 gene. Cancer Lett. 2015 Feb 1;357(1):105-113. doi: 10.1016/j.canlet.2014.11.002. Epub 2014 Nov 11.
• Ref 38: Long noncoding RNA UCA1 targets miR-582-5p and contributes to the progression and drug resistance of bladder cancer cells through ATG7-mediated autophagy inhibition. Onco Targets Ther. 2019 Jan 9;12:495-508. doi: 10.2147/OTT.S183940. eCollection 2019.
• Ref 39: Urothelial carcinoma with an NRF1-BRAF rearrangement and response to targeted therapyCold Spring Harb Mol Case Stud. 2019 Jun 3;5(3):a003848. doi: 10.1101/mcs.a003848. Print 2019 Jun.
• Ref 40: Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer modelsMol Cancer Ther. 2012 Mar;11(3):690-9. doi: 10.1158/1535-7163.MCT-11-0450. Epub 2012 Jan 11.
• Ref 41: Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR DysregulationPLoS One. 2016 Sep 14;11(9):e0162594. doi: 10.1371/journal.pone.0162594. eCollection 2016.
• Ref 42: Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinibCancer Biol Ther. 2014 Sep;15(9):1239-47. doi: 10.4161/cbt.29687. Epub 2014 Jul 14.
• Ref 43: The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitorMol Cancer Ther. 2014 Nov;13(11):2547-58. doi: 10.1158/1535-7163.MCT-14-0248. Epub 2014 Aug 28.
• Ref 44: The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder CancerClin Cancer Res. 2017 Nov 1;23(21):6580-6591. doi: 10.1158/1078-0432.CCR-17-0033. Epub 2017 Aug 14.
• Ref 45: miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. Oncogene. 2013 Sep 26;32(39):4694-701. doi: 10.1038/onc.2012.483. Epub 2012 Oct 22.
• Ref 46: Mutant HRAS as novel target for MEK and mTOR inhibitorsOncotarget. 2015 Dec 8;6(39):42183-96. doi: 10.18632/oncotarget.5619.
• Ref 47: Inhibition of RAS function through targeting an allosteric regulatory siteNat Chem Biol. 2017 Jan;13(1):62-68. doi: 10.1038/nchembio.2231. Epub 2016 Nov 7.
• Ref 48: Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in miceJ Clin Invest. 2009 May;119(5):1216-29. doi: 10.1172/JCI38017. Epub 2009 Apr 20.
• Ref 49: Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer. Cancer Discov. 2013 Sep;3(9):1058-71. doi: 10.1158/2159-8290.CD-12-0569. Epub 2013 Jun 6.