Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer

Abstract

Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that MET^D1228V induces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response.

Significance: With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired MET^D1228V mutation mediates resistance to type I, but not type II, MET inhibitors, having therapeutic implications for the clinical use of sequential MET inhibitors. Cancer Discov; 6(12); 1334-41. ©2016 AACR.See related commentary by Trusolino, p. 1306This article is highlighted in the In This Issue feature, p. 1293.

Figure 1

Response and resistance to savolitinib and osimertinib a patient with EGFR-mutant NSCLC harboring MET amplification. A, treatment timeline. B, despite being refractory to prior EGFR inhibitors, a dramatic response to the combination was seen after 4 weeks. C, after 36 weeks on therapy, an isolated lung nodule appeared and was resected, however further progression was seen. D, serial plasma genotyping demonstrates response of the known EGFR exon 19 deletion followed by progression with development of an acquired D1228V mutation, in the absence of EGFR T790M.

Figure 2

Simulations of savolitinib (A, B) and cabozantinib (C, D) binding to the wildtype (A, C) and mutant (B, D) MET kinase. Kinase inhibitors are shown in green and amino acids are shown in yellow. A, savolitinib binding to wildtype MET relies upon a π-π interaction with Y1230 in the activation loop (blue line), stabilized by a salt bridge between D1228 and K1110. B, MET D1228V results in loss of this salt bridge, resulting in repositioning of Y1230 and loss of π-π stacking (blue line). C, cabozantinib binds to the inactive conformation of wildtype MET and does not rely upon this π-π interaction with Y1230. D, cabozantinib binding is not impacted by V1228 which is remote from the drug binding sites.

Figure 3

MET D1228V causes resistance to type I MET inhibitors, while sensitivity to type II MET inhibitors is maintained. A, MET D1228V reduces the ability of type I MET kinase inhibitors (black) to dephosphorylate MET, but does not impact the activity of type II MET kinase inhibitors (blue). B, MTS growth inhibition assay of TPR-MET^WT or TPR-MET^D1228V transformed Ba/F3 cells exposed to dose-escalated savolitinib or cabozantinib shows differential sensitivity of TPR-MET^D1228V. C, MTS growth inhibition assay of TPR-MET^WT or TPR-MET^D1228V transduced PC9 cells exposed to dose-escalated gefitinib alone or in combination with savolitinib or cabozantinib shows differential sensitivity of TPR-MET^D1228V PC9 to the MET inhibitors. D, TPR-MET D1228V reduces the ability of savolitinib to dephosphorylate TPR-MET and inhibit downstream signaling in combination with gefitinib, but does not impact the activity of cabozantinib in combination with gefitinib. E, as predicted, the cancer exhibited a response after 4 weeks of cabozantinib combined with erlotinib. Abbreviations: Gef., gefitinib; Sav., savolitinib; Cab., cabozantinib