PRJNA842210
METex14 addiction and MET inhibitor sensitivity relie on Hepatocyte Growth Factor in 16HBE cells- part 2
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.