In vitro effectiveness of CB469, a MET tyrosine kinase inhibitor in MET-activated cancer cells

Abstract

Gene alterations in receptor tyrosine kinases can result in oncogenic driver mutation in non-small cell lung cancer (NSCLC) including in genes like EGFR, ALK and MET. MET amplifications and MET exon14 skipping are the primary genetic changes in MET-altered cancers. Acquired MET mutations mediate resistance to clinical MET-targeted therapy in NSCLC. MET kinase domain secondary mutations (D1228X, Y1230X) confer resistance to type I MET tyrosine kinase inhibitors (TKIs) in METexon14-altered or MET amplified NSCLC. Here, we investigated the preclinical activity of a novel MET inhibitor, CB469, with cell growth, signaling pathway and colony formation. We confirmed that CB469 inhibited the activity of MET wild and secondary mutant kinases, D1228N and Y1230H, as a type II inhibitor. CB469 also inhibited cell growth and cell signaling proteins in MET-activated or MET exon14 skipping-mutated cancer cell lines and NIH/3T3 cells expressing an engineered MET mutant. CB469 exhibited the inhibitory efficacy comparable with that of capmatinib in migration of EBC-1(METwt) and Hs746T(METΔex14) cells. Finally, CB469 showed selective and potent inhibition in MET-activated cancer cells among MET TKIs leading to enhanced selectivity for MET-mutant versus wild type MET with inhibition of cell growth in NIH/3T3 cells expressing an engineered MET mutant variant.