Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

doi:10.1016/j.celrep.2019.06.026

	Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors
	Wang, Yuetong 1,2,3,10; Zhang, Jian 1,2,3,10; Ren, Shengxiang 4; Sun, Dan 1,2,3; Huang, Hsin-Yi 1,2,3; Wang, Hua 1,2,3; Jin, Yujuan 1,2,3; Li, Fuming 1,2,3; Zheng, Chao 1,2,3; Yang, Liu 1,2,3; Deng, Lei 5; Jiang, Zhonglin 1,10; Jiang, Tao 4; Han, Xiangkun 1,2,3; Hou, Shenda 1,2,3; Guo, Chenchen 1,2,3,10; Li, Fei 1,2,3; Gao, Dong 1,2,3; Qin, Jun 2,6,10; Gao, Daming 1,2,3; Chen, Luonan 1,2,3; Lin, Shu-Hai 7; Wong, Kwok-Kin 8; Li, Cheng 5; Hu, Liang 1,2,3; Zhou, Caicun 4; Ji, Hongbin1,2,3,4,9,10
	2019-07-09
发表期刊	CELL REPORTS (IF:7.5[JCR-2023],8.5[5-Year])
ISSN	2211-1247
卷号	28 期号:2 页码:512-+
发表状态	已发表
DOI	10.1016/j.celrep.2019.06.026
摘要	Drug resistance is a significant hindrance to effective cancer treatment. Although resistance mechanisms of epidermal growth factor receptor (EGFR) mutant cancer cells to lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, how cancer cells orchestrate adaptive response under sublethal drug challenge remains largely unknown. Here, we find that 2-h sublethal TKI treatment elicits a transient drug-tolerant state in EGFR mutant lung cancer cells. Continuous sublethal treatment reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive process involves H3K9 demethylation-mediated upregulation of branched-chain amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. Combination treatment with TKI- and ROS-inducing reagents overcomes this drug resistance in preclinical mouse models. Clinical information analyses support the correlation of BCAT1 expression with the EGFR TKI response. Our findings reveal the importance of BCAT1-engaged metabolism reprogramming in TKI resistance in lung cancer.
收录类别	SCI ; SCIE
语种	英语
资助项目	China Postdoctoral Science Foundation[2016M601667]
WOS研究方向	Cell Biology
WOS类目	Cell Biology
WOS记录号	WOS:000474580800019
出版者	CELL PRESS
WOS关键词	CANCER PROGRESSION ; BCAT1 PROMOTES ; GROWTH ; EXPRESSION ; PLASTICITY ; CELLS ; ROS
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/61118
专题	生命科学与技术学院_特聘教授组_季红斌组
通讯作者	Li, Cheng; Hu, Liang; Zhou, Caicun; Ji, Hongbin
作者单位	1.Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Cell Biol, Shanghai 200031, Peoples R China 2.Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China 3.Chinese Acad Sci, Innovat Ctr Cell Signaling Network, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China 4.Tongji Univ, Shanghai Pulm Hosp, Sch Med, Shanghai 200433, Peoples R China 5.Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China 6.Chinese Acad Sci, Inst Hlth Sci, Shanghai Inst Biol Sci, Key Lab Stem Cell Biol, Shanghai 200031, Peoples R China 7.Xiamen Univ, Innovat Ctr Cell Signaling Network, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China 8.Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA 9.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China 10.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Wang, Yuetong,Zhang, Jian,Ren, Shengxiang,et al. Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors[J]. CELL REPORTS,2019,28(2):512-+.
APA	Wang, Yuetong.,Zhang, Jian.,Ren, Shengxiang.,Sun, Dan.,Huang, Hsin-Yi.,...&Ji, Hongbin.(2019).Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors.CELL REPORTS,28(2),512-+.
MLA	Wang, Yuetong,et al."Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors".CELL REPORTS 28.2(2019):512-+.