LAUSR

Simple Summary MET exon 14 splice-site mutations occur in ~3–4% of lung adenocarcinoma cases, defining a cohort of patients which might benefit from anti-MET targeted therapy. Such therapies have yielded mixed results, however, pointing to the need for better treatment design. Our study sought to aid this by characterizing key changes in mutant MET signaling behaviour. We first compared the transcriptional profiles of lung tumours with either METΔex14 or wild-type MET-amplification. METΔex14-mutant tumours exhibited increased activation of the Ras-MAPK pathway, consistent with our observations in an isogenic model system. Furthermore, sustained activity of this pathway is necessary for proliferation and maintenance of METΔex14 tumours, while forced reactivation of this pathway is sufficient to restore growth in the absence of MET activity. Our findings suggest that the MAPK pathway represents a main effector of METΔex14-driven cancer, lending credence to the possibility of combined MET-MAPK inhibition to improve therapeutic outcomes. Abstract Targeted therapies for MET exon 14-skipping (METΔex14)-driven lung cancers have generated some promising results but response rates remain below that seen for other kinase-driven cancers. One strategy for improving treatment outcomes is to employ rational combination therapies to enhance the suppression of tumour growth and delay or prevent the emergence of resistance. To this end, we profiled the transcriptomes of MET-addicted lung tumours and cell lines and identified the RAS-mitogen-activated protein kinase (MAPK) pathway as a critical effector required for METΔex14-dependent growth. Ectopic expression of MET in an isogenic cell line model showed that overexpression of the mutant MET receptor led to higher levels of MAPK phosphorylation and nuclear import, resulting in increased expression and phosphorylation of nuclear MAPK targets. In comparison, other known MET effectors were unaffected. Inhibition of this pathway by KRAS knockdown in MET-addicted cells in vitro led to decreased viability in only the METΔex14-mutant cells. Conversely, decoupling RAS-MAPK axis, but not other effector pathways, from MET activity via the introduction of constitutively active mutants conferred resistance to MET inhibitors in vitro. Our results suggest that aberrant hyperactivity of the MET receptor caused by the exon 14-skipping mutation does not uniformly upregulate all known downstream effectors, rather gaining a predilection for aberrantly activating and subsequently relying on the RAS-MAPK pathway. These findings provide a rationale for the co-targeting of the RAS-MAPK pathway alongside MET to prolong therapeutic response and circumvent resistance to improve patient survival.