Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14-mutant Non-small Cell Lung Cancer

PURPOSE: MET exon 14 splice site alterations that cause exon skipping at the mRNA level (METex14) are actionable oncogenic drivers amenable to therapy with MET tyrosine kinase inhibitors (TKI); however, secondary resistance eventually arises in most cases while other tumors display primary resistance. Beyond relatively uncommon on-target MET kinase domain mutations, mechanisms underlying primary and acquired resistance remain unclear. EXPERIMENTAL DESIGN: We examined clinical and genomic data from 113 lung cancer patients with METex14. MET TKI resistance due to KRAS mutation was functionally evaluated using in vivo and in vitro models. RESULTS: Five of 113 patients (4.4%) with METex14 had concurrent KRAS G12 mutations, a rate of KRAS co-occurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the KRAS mutation was acquired post-crizotinib, while the remaining 4 METex14 patients harbored the KRAS mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with METex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that KRAS mutation results in constitutive activation of RAS/ERK signaling and resistance to MET inhibition. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. CONCLUSIONS: KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in METex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort. (245/250 words) TRANSLATIONAL RELEVANCE: METex14 alterations have emerged as one of the most common targetable alterations in non-small cell lung cancers, and are amenable to MET kinase inhibitor therapy; however, inhibitor activity can be limited by primary or acquired genomic aberrations that lead to therapeutic resistance, warranting the investigation of alternative therapeutic approaches. We show that concurrent KRAS mutation is more common in the setting of METex14 than with other major drivers (e.g. sensitizing EGFR and ALK alterations), and confers primary or secondary resistance to MET-directed therapies in METex14-altered lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK reduced growth of cell line and xenograft models. These results provide a rationale for clinical evaluation of these combination approaches. (115/120–150 words)