2. Academic Validation
  3. Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

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

  • Cell Rep. 2019 Jul 9;28(2):512-525.e6. doi: 10.1016/j.celrep.2019.06.026.
Yuetong Wang 1,  Jian Zhang 1,  Shengxiang Ren 2,  Dan Sun 3,  Hsin-Yi Huang 3,  Hua Wang 3,  Yujuan Jin 3,  Fuming Li 3,  Chao Zheng 3,  Liu Yang 3,  Lei Deng 4,  Zhonglin Jiang 5,  Tao Jiang 2,  Xiangkun Han 3,  Shenda Hou 3,  Chenchen Guo 1,  Fei Li 3,  Dong Gao 3,  Jun Qin 6,  Daming Gao 3,  Luonan Chen 3,  Shu-Hai Lin 7,  Kwok-Kin Wong 8,  Cheng Li 9,  Liang Hu 10,  Caicun Zhou 11,  Hongbin Ji 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 3 State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 4 School of Life Sciences, Peking University, Beijing 100871, China.
  • 5 State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 6 CAS Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 7 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 9 School of Life Sciences, Peking University, Beijing 100871, China. Electronic address: cheng_li@pku.edu.cn.
  • 10 State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: liang.hu@sibcb.ac.cn.
  • 11 Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: caicunzhou@aliyun.com.
  • 12 State Key Laboratory of Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; CAS Center for Excellence in Molecular Cell Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: hbji@sibcb.ac.cn.
PMID: 31291585 DOI: 10.1016/j.celrep.2019.06.026
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.

Keywords

BCAT1; EGFR tyrosine kinase inhibitors; branched-chain amino acids; drug resistance; lung cancer; metabolic reprogramming.

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