Activation of KRAS mediates resistance to targeted therapy in MET ex on 14 mutant non-small cell lung cancer

Purpose: MET exon 14 splice site alterations that cause exon skipping at the mRNA level (MET 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. Experimental Design: We examined clinical and genomic data from 113 lung cancer patients with MET ex14. 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 MET ex14 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 MET ex14 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 MET ex14 lung cancers. Dual inhibition of MET or EGFR/ERBB2 and MEK may represent a potential therapeutic approach in this molecular cohort.

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