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
  • 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. [email protected].
  • 10. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. [email protected].
  • 11. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China. [email protected].
  • 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. [email protected].
  • 13. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 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. [email protected].
  • 15. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 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. [email protected].
  • 17. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 18. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. [email protected].
  • # 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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