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

• DOI: 10.1158/1078-0432.c.7234920.v1
• Publication Date: 2024-05-15T07:44:47Z
• Authors: Eranga R. Balasoo...; Qibiao Wu; Haley Ellis; Yuanli Zhen; Bryanna L. Norden; Ryan B. Corcoran; Adithi Mohan; Eric Martin; Aleksandra Franovic; John Tyhonas; Matthew Lardy; Kathryn B. Grandi...; Robert Pelham; Liliana Soroceanu; Vanessa S. Silveira; Nabeel Bardeesy
• Keywords: Protein kinase domain

<div>AbstractPurpose:<p>FGFR2 and FGFR3 show oncogenic activation in many cancer types, often through chromosomal fusion or extracellular domain mutation. FGFR2 alterations are most prevalent intrahepatic cholangiocarcinoma (ICC) bladder cancers, respectively, multiple selective reversible covalent pan-FGFR tyrosine kinase inhibitors (TKI) have been approved these contexts. However, resistance, due to acquired secondary mutations the FGFR2/3 domain, limits efficacy. Resistance is typically polyclonal, involving a spectrum of different that frequently affect molecular brake gatekeeper residues (N550 V565 FGFR2).</p>Experimental Design:<p>Here, we characterize activity next-generation FGFR inhibitor, KIN-3248, preclinical models fusion<sup>+</sup> ICC harboring series mutations, <i>in vitro</i> vivo</i>. We also test select alleles models.</p>Results:<p>KIN-3248 exhibits potent selectivity for FGFR1–3 retains against various addition being effective V555M N540K mutations. Notably, KIN-3248 extends V565F mutation, which causes profound resistance currently inhibitors. Combination treatment with EGFR MEK potentiates efficacy vivo</i>, including mutations.</p>Conclusions:<p>Thus, novel FGFR1–4 inhibitor whose distinct profile highlights its potential other FGFR-driven cancers.</p></div>