| Title | Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors |
| Authors | Wang, Yuetong Zhang, Jian Ren, Shengxiang Sun, Dan Huang, Hsin-Yi Wang, Hua Jin, Yujuan Li, Fuming Zheng, Chao Yang, Liu Deng, Lei Jiang, Zhonglin Jiang, Tao Han, Xiangkun Hou, Shenda Guo, Chenchen Li, Fei Gao, Dong Qin, Jun Gao, Daming Chen, Luonan Lin, Shu-Hai Wong, Kwok-Kin Li, Cheng Hu, Liang Zhou, Caicun Ji, Hongbin |
| Affiliation | Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Cell Biol, Shanghai 200031, Peoples R China Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China Chinese Acad Sci, Innovat Ctr Cell Signaling Network, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China Tongji Univ, Shanghai Pulm Hosp, Sch Med, Shanghai 200433, Peoples R China Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China Chinese Acad Sci, Inst Hlth Sci, Shanghai Inst Biol Sci, Key Lab Stem Cell Biol, Shanghai 200031, Peoples R China Xiamen Univ, Innovat Ctr Cell Signaling Network, Sch Life Sci, State Key Lab Cellular Stress Biol, Xiamen 361102, Fujian, Peoples R China Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200120, Peoples R China Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| Issue Date | 2019 |
| Publisher | CELL REPORTS |
| Abstract | 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. |
| URI | http://hdl.handle.net/20.500.11897/546769 |
| ISSN | 2211-1247 |
| DOI | 10.1016/j.celrep.2019.06.026 |
| Indexed | SCI(E) EI |
| Appears in Collections: | 生命科学学院 |
