The Irreversible FGFR Inhibitor KIN-3248 Overcomes FGFR2 Kinase Domain Mutations

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Fibroblast Growth Factor Receptors (FGFRs) are frequently activated in cancers like intrahepatic cholangiocarcinoma (ICC) and bladder cancer.
• Approved FGFR tyrosine kinase inhibitors (TKIs) face resistance due to secondary kinase domain mutations, limiting treatment efficacy.

Purpose of the Study:

• To characterize the preclinical activity of KIN-3248, a next-generation covalent pan-FGFR inhibitor.
• To evaluate KIN-3248 against FGFR2 and FGFR3 mutations, including those conferring resistance to existing therapies.

Main Methods:

• In vitro and in vivo preclinical models of FGFR2 fusion-positive ICC with secondary kinase domain mutations.
• Testing of select FGFR3 alleles in bladder cancer models.
• Assessment of KIN-3248 activity against various FGFR2 and FGFR3 mutations, including gatekeeper mutations.

Main Results:

• KIN-3248 demonstrated potent selectivity for FGFR1-3 and retained activity against multiple FGFR2 kinase domain mutations.
• The inhibitor was effective against FGFR3 mutations (V555M, N540K) and the FGFR2 V565F gatekeeper mutation, a key resistance mechanism.
• Combination therapy with EGFR or MEK inhibitors enhanced KIN-3248 efficacy in vivo.

Conclusions:

• KIN-3248 is a novel FGFR1-4 inhibitor with a distinct activity profile against FGFR kinase domain mutations.
• Its ability to overcome resistance mutations highlights its potential therapeutic value for ICC and other FGFR-driven malignancies.