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

exon 14 splice site alterations that cause exon skipping at the mRNA level ( ex14) 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. We examined clinical and genomic data from 113 patients with lung cancer with ex14. MET TKI resistance due to mutation was functionally evaluated using and models. Five of 113 patients (4.4%) with ex14 had concurrent G12 mutations, a rate of cooccurrence significantly higher than in other major driver-defined lung cancer subsets. In one patient, the mutation was acquired post-crizotinib, while the remaining 4 ex14 patients harbored the mutation prior to MET TKI therapy. Gene set enrichment analysis of transcriptomic data from lung cancers with ex14 revealed preferential activation of the KRAS pathway. Moreover, expression of oncogenic KRAS enhanced MET expression. Using isogenic and patient-derived models, we show that 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. mutation is a recurrent mechanism of primary and secondary resistance to MET TKIs in ex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.