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Bahcall, Magda; Paweletz, Cloud P; Kuang, Yanan; Taus, Luke J; Sim, Taebo; Kim, Nam Doo; Dholakia, Kshiti H; Lau, Christie J; Gokhale, Prafulla C; Chopade, Pratik R; Hong, Fangxin; Wei, Zihan; Köhler, Jens; Kirschmeier, Paul T; Guo, Jiannan; Guo, Sujuan; Wang, Stephen; Jänne, Pasi A
Molecular cancer therapeutics, 02/2022, Volume: 21, Issue: 2Journal Article
MET-targeted therapies are clinically effective in -amplified and exon 14 deletion mutant ( ex14) non-small cell lung cancers (NSCLCs), but their efficacy is limited by the development of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs) (type I/II) have been developed or are under clinical evaluation, which may overcome MET-mediated drug resistance mechanisms. In this study, we assess secondary MET mutations likely to emerge in response to treatment with single-agent or combinations of type I/type II MET TKIs using TPR-MET transformed Ba/F3 cell mutagenesis assays. We found that these inhibitors gave rise to distinct secondary MET mutant profiles. However, a combination of type I/II TKI inhibitors (capmatinib and merestinib) yielded no resistant clones The combination of capmatinib/merestinib was evaluated and led to a significant reduction in tumor outgrowth compared with either MET inhibitor alone. Our findings demonstrate and that a simultaneous treatment with a type I and type II MET TKI may be a clinically viable approach to delay and/or diminish the emergence of on target MET-mediated drug-resistance mutations.
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