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Ref Type Journal Article
PMID (21119661)
Authors Lamont FR, Tomlinson DC, Cooper PA, Shnyder SD, Chester JD, Knowles MA
Title Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo.
Journal British journal of cancer
Vol 104
Issue 1
Date 2011 Jan 04
URL
Abstract Text Activating mutations of FGFR3 are frequently identified in superficial urothelial carcinoma (UC) and increased expression of FGFR1 and FGFR3 are common in both superficial and invasive UC.The effects of inhibition of receptor activity by three small molecule inhibitors (PD173074, TKI-258 and SU5402) were investigated in a panel of bladder tumour cell lines with known FGFR expression levels and FGFR3 mutation status.All inhibitors prevented activation of FGFR3, and inhibited downstream MAPK pathway signalling. Response was related to FGFR3 and/or FGFR1 expression levels. Cell lines with the highest levels of FGFR expression showed the greatest response and little or no effect was measured in normal human urothelial cells or in UC cell lines with activating RAS gene mutations. In sensitive cell lines, the drugs induced cell cycle arrest and/or apoptosis. IC(50) values for PD173074 and TKI-258 were in the nanomolar concentration range compared with micromolar concentrations for SU5402. PD173074 showed the greatest effects in vitro and in vivo significantly delayed the growth of subcutaneous bladder tumour xenografts.These results indicate that inhibition of FGFR1 and wild-type or mutant FGFR3 may represent a useful therapeutic approach in patients with both non-muscle invasive and muscle invasive UC.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SU5402 SU5402 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SU5402 SU 5402 FGFR1 Inhibitor 24 FGFR2 Inhibitor 18 FGFR3 Inhibitor 13 VEGFR Inhibitor (Pan) 33 SU5402 is an ATP-competitive inhibitor of FGFR1, FGFR2, FGFR3, and VEGFR, which may inhibit cell proliferation and reduce cell migration (PMID: 21119661, PMID: 23420874, PMID: 18852144, PMID: 32409632).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 - TACC3 urinary bladder cancer sensitive SU5402 Preclinical Actionable In a preclinical study, SU5402 induced cell-cycle arrest and inhibited proliferation of bladder cancer cells that have been demonstrated to harbor FGFR3-TACC3 in culture (PMID: 21119661, PMID: 23175443). 21119661 23175443
FGFR3 over exp urinary bladder cancer sensitive SU5402 Preclinical Actionable In a preclinical study, SU5402 inhibited growth of bladder cancer cells over expressing wild-type FGFR3 in culture (PMID: 21119661). 21119661