Acquired MET Y1248H and D1246N mutations mediate resistance to MET inhibitors in non-small cell lung cancer

Purpose: MET amplification, responsible for 20% of acquired resistance to epidermal growth factor receptor (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 MET mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs-induced resistance remains elusive. <p>Experimental Design: 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 plasms ctDNA samples to detect and quantify genetic alterations.</p> <p>Results: We identified 2 newly acquired MET mutations Y1248H and D1246N in 2 patients and further confirmed their resistance against Type I MET-TKIs in silco, in vitro and in vivo. 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-TKIs resistance mechanism.</p> <p>Conclusion Our study provides insight into the diversity of mechanisms underlying MET-TKI induced resistance and highlights the potential of sequential use of MET-TKIs.

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