2. Academic Validation
  3. Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation

Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation

  • Signal Transduct Target Ther. 2024 Aug 15;9(1):216. doi: 10.1038/s41392-024-01928-8.
Tao Zhang # 1,  Zilu Pan # 1 2,  Jing Gao # 1,  Qingqing Wu # 3,  Gang Bai 1,  Yan Li 1,  Linjiang Tong 1,  Fang Feng 1,  Mengzhen Lai 1,  Yingqiang Liu 1,  Peiran Song 3,  Yi Ning 1,  Haotian Tang 1,  Wen Luo 3 4,  Yi Chen 1 2,  Yan Fang 1 2,  Hui Zhang 5,  Qiupei Liu 1 6,  Yudi Zhang 1 2 7,  Hua Wang 2 8,  Zhiwei Chen 1 2,  Yi Chen 1,  Meiyu Geng 1 2,  Hongbin Ji 2 8,  Guilong Zhao 9 10 11,  Hu Zhou 12 13,  Jian Ding 14 15,  Hua Xie 16 17 18
Affiliations

Affiliations

  • 1 Division of Antitumor Pharmacology & Analytical Research Center for Organic and Biological Molecules & State Key Laboratory of Drug Research & Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
  • 4 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
  • 5 Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Department of Chemical and Environmental Engineering, University of Nottingham, Ningbo, China.
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 8 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 9 Division of Antitumor Pharmacology & Analytical Research Center for Organic and Biological Molecules & State Key Laboratory of Drug Research & Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhaoguilong@simm.ac.cn.
  • 10 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. zhaoguilong@simm.ac.cn.
  • 11 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. zhaoguilong@simm.ac.cn.
  • 12 Division of Antitumor Pharmacology & Analytical Research Center for Organic and Biological Molecules & State Key Laboratory of Drug Research & Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. zhouhu@simm.ac.cn.
  • 13 University of Chinese Academy of Sciences, Beijing, China. zhouhu@simm.ac.cn.
  • 14 Division of Antitumor Pharmacology & Analytical Research Center for Organic and Biological Molecules & State Key Laboratory of Drug Research & Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. jding@simm.ac.cn.
  • 15 University of Chinese Academy of Sciences, Beijing, China. jding@simm.ac.cn.
  • 16 Division of Antitumor Pharmacology & Analytical Research Center for Organic and Biological Molecules & State Key Laboratory of Drug Research & Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. hxie@simm.ac.cn.
  • 17 University of Chinese Academy of Sciences, Beijing, China. hxie@simm.ac.cn.
  • 18 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. hxie@simm.ac.cn.
  • # Contributed equally.
PMID: 39143065 DOI: 10.1038/s41392-024-01928-8
Abstract

Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung Cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung Cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

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