Acquired MET Y1248H and D1246N Mutations Mediate Resistance to MET Inhibitors in Non–Small Cell Lung Cancer
| Autor: | Si-Yang Liu, Qing Zhou, Lan-Ying Gou, A. Li, Zhi-Hong Chen, Bin Gan, Hua-Jun Chen, Bin-Chao Wang, Jian Su, Chong-Rui Xu, Qi Zhang, Jin-Ji Yang, Zheng Wang, Xue-Ning Yang, Zhenfan Yang, Shannon Chuai, Han Han-Zhang, Zhen Wang, Zhi Xie, Wen-Zhao Zhong, Zhou Zhang, Yu Bai, Xu-Chao Zhang, Si-Pei Wu, Ben-Yuan Jiang, Hong-Fei Gao, Yi-Long Wu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Mutation Cancer Drug resistance Biology Bioinformatics medicine.disease_cause medicine.disease In vitro respiratory tract diseases 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Gefitinib Oncology In vivo 030220 oncology & carcinogenesis medicine Cancer research Carcinoma Lung cancer medicine.drug |
| Zdroj: | Clinical Cancer Research. 23:4929-4937 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | 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. Clin Cancer Res; 23(16); 4929–37. ©2017 AACR. |
| Databáze: | OpenAIRE |
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