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

Abstract

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 patients with lung cancer 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 cooccurrence 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. a KRAS known hotspot mutation (M) or KRAS amplification (A); or both KRAS mutation and amplification. b Fisher exact test for prevalence of concurrent KRAS alterations in indicated subset compared with aggregate of the other driver subsets in the table. c Defined as known oncogenic alterations in L858R and exon 19 deletion/insertions. Suzawa et al.

Crizotinib inMET-Deregulated orROS1-Rearranged Pretreated Non–Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial

“…Additional studies confirmed that MET deregulation, including overexpression, gene copy number gain or mutation, confers an aggressive phenotype (33). In addition to an aggressive behavior, also reinforced by the scarce sensitivity to prior chemotherapy, MET-deregulated NSCLC demonstrated modest and transient responsiveness to crizotinib, suggesting that other factors could modulate sensitivity to MET-inhibition, such as cooccurrence of driver events or expression of the MET protein as recently reported (33)(34)(35)(36). Particularly, in a context of MET amplification, Tong and colleagues demonstrated that low levels of amplification may occur in a background of KRAS mutation, while high levels of MET amplification were mutually exclusive with major oncogene drivers (33).…”

Non-Coding RNAs in Lung Tumor Initiation and Progression

“…Others have found that targeting of c-MET with miR-19a [209] and miR-409-3p [210] could inhibit downstream signaling of the Akt signaling pathway as well. Due to crosstalk between KRAS/MET and EGFR/MET, dual targeting of these signaling pathways via non-coding RNAs could potentially predict drug sensitivity, biomarker potential, and prognostic value [237,238].…”

Acquired Mechanism of Crizotinib Resistance in NSCLC with MET Exon 14 Skipping

“…2 The efficacy of crizotinib in lung cancer with a MET exon 14 skipping mutation has been demonstrated, but resistance is inevitable. 3 Here we have reported a patient with advanced lung cancer with a MET exon 14 skipping mutation and a MET exon 5 C526F mutation. After the patient progressed through crizotinib treatment, orally administered cabozantinib was effective.…”