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Ref Type Journal Article
PMID (38437671)
Authors Balasooriya ER, Wu Q, Ellis H, Zhen Y, Norden BL, Corcoran RB, Mohan A, Martin E, Franovic A, Tyhonas J, Lardy M, Grandinetti KB, Pelham R, Soroceanu L, Silveira VS, Bardeesy N
Title The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 30 10 2024 May 15 2181-2192 Clin Cancer Res
URL
Abstract Text FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 and FGFR3 alterations are most prevalent in intrahepatic cholangiocarcinoma (ICC) and bladder cancers, respectively, and multiple selective reversible and covalent pan-FGFR tyrosine kinase inhibitors (TKI) have been approved in these contexts. However, resistance, often due to acquired secondary mutations in the FGFR2/3 kinase domain, limits efficacy. Resistance is typically polyclonal, involving a spectrum of different mutations that most frequently affect the molecular brake and gatekeeper residues (N550 and V565 in FGFR2).Here, we characterize the activity of the next-generation covalent FGFR inhibitor, KIN-3248, in preclinical models of FGFR2 fusion+ ICC harboring a series of secondary kinase domain mutations, in vitro and in vivo. We also test select FGFR3 alleles in bladder cancer models.KIN-3248 exhibits potent selectivity for FGFR1-3 and retains activity against various FGFR2 kinase domain mutations, in addition to being effective against FGFR3 V555M and N540K mutations. Notably, KIN-3248 activity extends to the FGFR2 V565F gatekeeper mutation, which causes profound resistance to currently approved FGFR inhibitors. Combination treatment with EGFR or MEK inhibitors potentiates KIN-3248 efficacy in vivo, including in models harboring FGFR2 kinase domain mutations.Thus, KIN-3248 is a novel FGFR1-4 inhibitor whose distinct activity profile against FGFR kinase domain mutations highlights its potential for the treatment of ICC and other FGFR-driven cancers.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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 S249C FGFR3 V555M urinary bladder cancer resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, a bladder cancer cell line harboring FGFR3 S249C and expressing FGFR3 V555M was resistant to Truseltiq (infigratinib) in culture (PMID: 38437671). 38437671
FGFR2 N550H Advanced Solid Tumor predicted - sensitive KIN-3248 Preclinical - Biochemical Actionable In a preclinical study, KIN-3248 inhibited kinase activity of FGFR2 N550H in an in vitro assay (PMID: 38437671). 38437671
FGFR3 S249C FGFR3 V555M urinary bladder cancer resistant Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, a bladder cancer cell line harboring FGFR3 S249C and expressing FGFR3 V555M was resistant to Pemazyre (pemigatinib) in culture (PMID: 38437671). 38437671
FGFR3 S249C FGFR3 V555M urinary bladder cancer sensitive KIN-3248 Preclinical - Cell culture Actionable In a preclinical study, KIN-3248 inhibited viability of a bladder cancer cell line harboring FGFR3 S249C and expressing FGFR3 V555M in culture (PMID: 38437671). 38437671
FGFR3 S249C FGFR3 N540K intrahepatic cholangiocarcinoma predicted - sensitive Futibatinib Preclinical - Cell culture Actionable In a preclinical study, Lytgobi (futibatinib) inhibited viability of a bladder cancer cell line harboring FGFR3 S249C and expressing FGFR3 N540K in culture (PMID: 38437671). 38437671
FGFR3 S249C FGFR3 V555M urinary bladder cancer resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, a bladder cancer cell line harboring FGFR3 S249C and expressing FGFR3 V555M was resistant to Balversa (erdafitinib) in culture (PMID: 38437671). 38437671
FGFR3 S249C FGFR3 N540K urinary bladder cancer sensitive KIN-3248 Preclinical - Cell culture Actionable In a preclinical study, KIN-3248 inhibited viability of a bladder cancer cell line harboring FGFR3 S249C and expressing FGFR3 N540K in culture (PMID: 38437671). 38437671
FGFR3 K650M Advanced Solid Tumor predicted - sensitive KIN-3248 Preclinical - Biochemical Actionable In a preclinical study, KIN-3248 inhibited kinase activity of FGFR3 K650M in an in vitro assay (PMID: 38437671). 38437671
FGFR3 S249C FGFR3 N540K urinary bladder cancer resistant Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, a bladder cancer cell line harboring FGFR3 S249C and expressing FGFR3 N540K was resistant to Pemazyre (pemigatinib) in culture (PMID: 38437671). 38437671