Combination of Type I and Type II MET Tyrosine Kinase Inhibitors as Therapeutic Approach to Prevent Resistance

MET-targeted therapies have shown clinical efficacy in MET-amplified and MET exon 14 skipping mutation (METex14) non-small cell lung cancers (NSCLCs); however, their long-term benefit is often limited by the emergence of drug resistance. Structurally distinct MET tyrosine kinase inhibitors (TKIs)—classified as type I and type II—have been developed to address resistance mechanisms. In this study, we used TPR-MET-transformed Ba/F3 cell mutagenesis assays to evaluate secondary MET mutations arising in response to single-agent or combined type I and type II MET TKI treatments. Our results revealed that each inhibitor class selects for distinct resistance mutations. Notably, the combination of a type I TKI (capmatinib) and a type II TKI (merestinib) prevented the emergence of resistant clones in vitro. In vivo, this combination significantly suppressed tumor growth compared to either agent alone. These findings suggest that concurrent administration of type I and type II MET TKIs may represent an effective strategy to delay or prevent the development of on-target resistance mutations in MET-driven NSCLC.