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

Anna Li, Jin Ji Yang, Xu Chao Zhang, Zhou Zhang, Jian Su, Lan Ying Gou, Yu Bai, Qing Zhou, Zhenfan Yang, Han Han-Zhang, Wen Zhao Zhong, Shannon Chuai, Qi Zhang, Zhi Xie, Hongfei Gao, Huajun Chen, Zhen Wang, Zheng Wang, Xue Ning Yang, Bin Chao WangBin Gan, Zhi Hong Chen, Ben Yuan Jiang, Si Pei Wu, Si Yang Liu, Chong Rui Xu, Yi Long Wu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Purpose: MET 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 MET mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs–induced resistance remains elusive. 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 plasmas ctDNA samples to detect and quantify genetic alterations. 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-TKI resistance mechanism. Conclusions: Our study provides insight into the diversity of mechanisms underlying MET-TKI–induced resistance and highlights the potential of sequential use of MET-TKIs.

Original languageEnglish (US)
Pages (from-to)4929-4937
Number of pages9
JournalClinical Cancer Research
Issue number16
StatePublished - Aug 15 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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