METex14 addiction and MET inhibitor sensitivity relie on Hepatocyte Growth Factor

The exon skipping mutations of the receptor tyrosine kinase MET (METex14), leading to oncogenic MET, are increasingly reported in cancers, including in 3-4% of non-small cell lung cancer (NSCLC). MET Tyrosine Kinase Inhibitors (TKIs) have shown activity in these patients. However only half of the patients derive benefit from MET-TKIs, underlying the need for additional biomarkers. It is unclear whether METex14 alone is sufficient to drive tumorigenesis and sensitize tumors to TKI. Among studies, METex14 was reported either a driver mutation or requiring concomitant alterations for its oncogenicity; either constitutively active or ligand dependent. Using CRISPR/Cas9, we developed two isogenic human lung cell models expressing METex14 on its own in non-transformed cells or in presence of a pre-existing oncogenic KRAS mutation in transformed cells. We clearly demonstrate that METex14, with or without co-occurring oncogenic alterations, requires HGF for its activation and is a ligand-dependent oncogenic driver. Moreover, METex14 sensitizes KRAS-driven tumors to MET-TKI, suggesting the existence of an oncogenic switch. Interestingly, HGF was detected in tumor cells in half of NSCLC patient samples. Therefore, HGF may be considered as a potential predictive biomarker in future studies.