title: AcquiredMETY1248H and D1246N Mutations Mediate Resistance to MET Inhibitors in Non-Small Cell Lung Cancer.
abstract: Purpose:METamplification, 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 ofMETmutations 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 acquiredMETmutations, Y1248H and D1246N, in 2 patients and further confirmed their resistance against type I MET-TKIsin silco, in vitro, andin vivoInterestingly, 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.
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Anna
authors.initials: A
authors.lastname: Li
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Jin-Ji
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Xu-Chao
authors.initials: XC
authors.lastname: Zhang
authors.affiliation: Burning Rock Biotech, Guangzhou, Guangdong Province, P.R. China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Su
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Lan-Ying
authors.initials: LY
authors.lastname: Gou
authors.affiliation: Asia Innovative Medicines and Early Development, AstraZeneca, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Asia Innovative Medicines and Early Development, AstraZeneca, Shanghai, China.
authors.forename: Zhenfan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Burning Rock Biotech, Guangzhou, Guangdong Province, P.R. China.
authors.forename: Han
authors.initials: H
authors.lastname: Han-Zhang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Wen-Zhao
authors.initials: WZ
authors.lastname: Zhong
authors.affiliation: Burning Rock Biotech, Guangzhou, Guangdong Province, P.R. China.
authors.forename: Shannon
authors.initials: S
authors.lastname: Chuai
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Gao
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Huajun
authors.initials: H
authors.lastname: Chen
authors.affiliation: Asia Innovative Medicines and Early Development, AstraZeneca, Shanghai, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Yang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Bin-Chao
authors.initials: BC
authors.lastname: Wang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Gan
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Chen
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Ben-Yuan
authors.initials: BY
authors.lastname: Jiang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Si-Pei
authors.initials: SP
authors.lastname: Wu
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Si-Yang
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China.
authors.forename: Chong-Rui
authors.initials: CR
authors.lastname: Xu
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, P.R. China. syylwu@live.cn.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects*; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib