Homo sapiens Targeted Locus (Loci). Homo sapiens

Aberrant receptor tyrosine kinase (RTK) signaling is a well-documented driver of disease onset and progression across myriad cancer types, including non-small cell lung cancer (NSCLC), where the MET RTK contributes to tumor progression, maintenance and resistance to targeted therapies. Here we explore the therapeutic potential of savolitinib, a potent and selective MET inhibitor, in NSCLC. In vitro, savolitinib inhibits MET phosphorylation with nanomolar potency, and sensitivity positively correlates with blockade of PI3K/AKT and MAPK signaling as well as MYC down-regulation. In vivo, savolitinib induces dose-dependent inhibition of these pathways and significantly decreases tumor growth of MET-dependent xenograft models. To understand possible resistance mechanisms, we generated savolitinib resistance in MET-amplified NSCLC cell lines and analyzed individual clones.