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

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.

• Authors: Yuetong Wang, Jian Zhang, Shengxiang Ren, Dan Sun, Hsin-Yi Huang, Hua Wang, Yujuan Jin, Fuming Li, Chao Zheng, Liu Yang, Lei Deng, Zhonglin Jiang, Tao Jiang, Xiangkun Han, Shenda Hou, Chenchen Guo, Fei Li, Dong Gao, Jun Qin, Daming Gao, Luonan Chen, Shu-Hai Lin, Kwok-Kin Wong, Cheng Li, Liang Hu, Caicun Zhou, Hongbin Ji
• Journal: Cell reports (Cell Rep) Vol. 28 Issue 2 Pg. 512-525.e6 (07 09 2019) ISSN: 2211-1247 [Electronic] United States
• PMID: 31291585 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Amino Acids, Branched-Chain
• Protein Kinase Inhibitors
• EGFR protein, human
• ErbB Receptors

Topics

• Amino Acids, Branched-Chain (metabolism)
• Drug Resistance, Neoplasm
• ErbB Receptors (antagonists & inhibitors)
• Humans
• Protein Kinase Inhibitors (pharmacology, therapeutic use)