Reference Detail

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	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 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
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 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 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
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 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 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