Disease Information

General Information of the Disease (ID: DIS00385)

• Name: Urinary system cancer
• ICD: ICD-11: 2C95

Type(s) of Resistant Mechanism of This Disease

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Infigratinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [1]

• Sensitive Disease: Urinary system cancer [ICD-11: 2C95.Y]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: Infigratinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: UMUC14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: SNU16 cells; Ascites; Homo sapiens (Human); CVCL_0076
• In Vitro Model: OPM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: NCI-H2444 cells; Lung; Homo sapiens (Human); CVCL_1552
• In Vitro Model: NCI-H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• In Vitro Model: MFM-223 cells; Pleural effusion; Homo sapiens (Human); CVCL_1408
• In Vitro Model: DMS-114 cells; Lung; Homo sapiens (Human); CVCL_1174
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Mechanism Description: c-Myc functioned as the key downstream effector that preceded FGFR-MEK/ERK signaling in FGFR aberrant cancer. Disruption of c-Myc overrode the cell proliferation driven by constitutively active FGFR. FGFR inhibition in FGFR-addicted cancer facilitated c-Myc degradation via phosphorylating c-Myc at threonine 58. Ectopic expression of undegradable c-Myc mutant conferred resistance to FGFR inhibition both in vitro and in vivo. c-Myc level alteration stringently determined the response to FGFR inhibitors, as demonstrated in FGFR-responsive cancer subset, as well as cancers bearing acquired or de novo resistance to FGFR inhibition.

Clinical Trial Drug(s) 1 drug(s) in total

AZD-4547

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [1]

• Sensitive Disease: Urinary system cancer [ICD-11: 2C95.Y]
• Molecule Alteration: Missense mutation; p.S249C (c.746C>G)
• Sensitive Drug: AZD-4547
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: FGF/FGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: NCI-H520 cells; Lung; Homo sapiens (Human); CVCL_1566
• In Vitro Model: RT112 cells; Bladder; Homo sapiens (Human); CVCL_1670
• In Vitro Model: BaF3 cells; Bone; Mus musculus (Mouse); CVCL_0161
• In Vitro Model: KG-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0374
• In Vitro Model: KATO-3 cells; Gastric; Homo sapiens (Human); CVCL_0371
• In Vitro Model: UMUC14 cells; Kidney; Homo sapiens (Human); CVCL_2747
• In Vitro Model: SNU16 cells; Ascites; Homo sapiens (Human); CVCL_0076
• In Vitro Model: OPM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1625
• In Vitro Model: NCI-H2444 cells; Lung; Homo sapiens (Human); CVCL_1552
• In Vitro Model: NCI-H1581 cells; Lung; Homo sapiens (Human); CVCL_1479
• In Vitro Model: MFM-223 cells; Pleural effusion; Homo sapiens (Human); CVCL_1408
• In Vitro Model: DMS-114 cells; Lung; Homo sapiens (Human); CVCL_1174
• In Vivo Model: BALB/c nude mouse PDX model; Mus musculus
• Mechanism Description: c-Myc functioned as the key downstream effector that preceded FGFR-MEK/ERK signaling in FGFR aberrant cancer. Disruption of c-Myc overrode the cell proliferation driven by constitutively active FGFR. FGFR inhibition in FGFR-addicted cancer facilitated c-Myc degradation via phosphorylating c-Myc at threonine 58. Ectopic expression of undegradable c-Myc mutant conferred resistance to FGFR inhibition both in vitro and in vivo. c-Myc level alteration stringently determined the response to FGFR inhibitors, as demonstrated in FGFR-responsive cancer subset, as well as cancers bearing acquired or de novo resistance to FGFR inhibition.

References

• Ref 1: c-Myc Alteration Determines the Therapeutic Response to FGFR InhibitorsClin Cancer Res. 2017 Feb 15;23(4):974-984. doi: 10.1158/1078-0432.CCR-15-2448. Epub 2016 Jul 11.