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

Abstract

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