Acquired MET Y1248H and D1246N Mutations Mediate Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

Abstract

amplification, responsible for 20% of acquired resistance to EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC), presents an attractive target. Numerous studies have conferred susceptibility of mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs-induced resistance remains elusive. We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a type I MET-TKI. We performed capture-based targeted ultra-deep sequencing on serial tumor biopsies and plasmas ctDNA samples to detect and quantify genetic alterations. We identified 2 newly acquired mutations, Y1248H and D1246N, in 2 patients and further confirmed their resistance against type I MET-TKIs, and Interestingly, NIH3T3 cells harboring either mutation exhibited responses to type II MET-TKIs, suggesting sequential use of MET-TKIs may offer a more durable response. In addition, we also discovered that EGFR amplification may act as an alternative MET-TKI resistance mechanism. Our study provides insight into the diversity of mechanisms underlying MET-TKI-induced resistance and highlights the potential of sequential use of MET-TKIs. .

Krüppel‐like factor 4 promotes c‐Met amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer

“…Uncontrolled activation of c‐Met, such as c‐Met and HGF amplification or mutation, has been reported as an important cause of acquired resistance of NSCLC to EGFR‐TKI and is correlated with poor clinical outcomes . When binding to the receptor of c‐Met, HGF can phosphorylate c‐Met tyrosine kinase and subsequently activate the downstream ERBB3/PI3K/Akt signaling pathway, which promotes cell proliferation, migration, survival, and anti‐apoptosis effects . Moreover, c‐Met overexpression is also detected in NSCLC without EGFR‐TKI treatment .…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…Treatment of patients with crizotinib eventually leads to resistant mutations ( Figure 1F). Two mutations in the A loop D1246H/N [141][142][143][144][145] and Y1248H/C/S [141,[144][145][146] stabilize the active conformation of the A loop and decreases the efficacy of the drug [147]. At least one study identified the G1181R in addition to the Y1248 and D1246 mutations when an exon 14 skipping patient was treated with crizotinib [145].…”

“…Resistance mutations to capmatinib arise that disrupt the interaction of the drug with the kinase. Patients with MET amplification treated with gefitinib and capmatinib developed the D1246N and the Y1248H resistant mutations [144]. Molecular modeling showed that the mutant c-MET was sufficiently distorted to prohibit the binding of the drug.…”

Emerging uses of biomarkers in lung cancer management: molecular mechanisms of resistance

“…In a recent study, Li et al (86) reported two acquired MET mutations, Y1248H and D1246N, which can cause resistance against Type I MET-TKIs. It was also noted that EGFR amplification may act as an alternative METTKIs bypass resistance mechanism (86). Amplification of MET, amplification of K-RAS and activation of B-RAF or EGFR pathways have also been proposed as mechanisms of acquired resistance to MET TKIs (87)(88)(89).…”