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

文献类型：期刊论文

作者Zhang, Tao8,9,10; Pan, Zilu7,8,9,10; Gao, Jing8,9,10; Wu, Qingqing6; Bai, Gang8,9,10; Li, Yan8,9,10; Tong, Linjiang8,9,10; Feng, Fang8,9,10; Lai, Mengzhen8,9,10; Liu, Yingqiang8,9,10
刊名SIGNAL TRANSDUCTION AND TARGETED THERAPY
出版日期2024-08-15
卷号9期号:1页码:17
ISSN号2095-9907
DOI10.1038/s41392-024-01928-8
通讯作者Zhao, Guilong(zhaoguilong@simm.ac.cn) ; Zhou, Hu(zhouhu@simm.ac.cn) ; Ding, Jian(jding@simm.ac.cn) ; Xie, Hua(hxie@simm.ac.cn)
英文摘要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 (alpha-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.
WOS关键词ACQUIRED-RESISTANCE ; LUNG-CANCER ; METABOLISM ; BCAT1 ; INHIBITORS ; LETHALITY ; HALLMARKS ; REVEALS ; DRIVEN
资助项目National Natural Science Foundation of China (National Science Foundation of China)[82273948] ; National Natural Science Foundation of China (National Science Foundation of China)[81903638] ; National Natural Science Foundation of China[2021B0909050003] ; High-level Innovative Research Institute[SKLDR-2023-TT-01] ; High-level Innovative Research Institute[SIMM2205KF-09] ; High-level Innovative Research Institute[LG202103-02-02] ; State Key Laboratory of Drug Research[CASIMM0120225003-1] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[2021A1515010197] ; Institutes for Drug Discovery and Development, Chinese Academy of Sciences[2023A1515012259] ; Guangdong Basic and Applied Basic Research Foundation[200805173640573] ; Guangdong Basic and Applied Basic Research Foundation[210730214049987] ; Zhongshan Municipal Natural Science Foundation[SIMM0120231001] ; Project of Shanghai Institute of Materia Medica, Chinese Academy of Sciences
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
WOS记录号WOS:001290715700001
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/313017]  
专题新药研究国家重点实验室
通讯作者Zhao, Guilong; Zhou, Hu; Ding, Jian; Xie, Hua
作者单位1.Chinese Acad Sci, State Key Lab Cell Biol, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, Shanghai, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
3.Univ Nottingham, Dept Chem & Environm Engn, Ningbo, Peoples R China
4.Shanghai Jiao Tong Univ, Sch Med, Shanghai Chest Hosp, Shanghai Lung Canc Ctr, Shanghai, Peoples R China
5.Southern Med Univ, Sch Pharmaceut Sci, Guangzhou, Peoples R China
6.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
7.Univ Chinese Acad Sci, Beijing, Peoples R China
8.Shanghai Inst Mat Med, Chinese Acad Sci, Mol Drug Res Ctr, State Key Lab Drug Res & Small, Shanghai, Peoples R China
9.Chinese Acad Sci, Analyt Res Ctr Organ & Biol Mol, Shanghai, Peoples R China
10.Chinese Acad Sci, Div Antitumor Pharmacol, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Tao,Pan, Zilu,Gao, Jing,et al. Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2024,9(1):17.
APA Zhang, Tao.,Pan, Zilu.,Gao, Jing.,Wu, Qingqing.,Bai, Gang.,...&Xie, Hua.(2024).Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation.SIGNAL TRANSDUCTION AND TARGETED THERAPY,9(1),17.
MLA Zhang, Tao,et al."Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation".SIGNAL TRANSDUCTION AND TARGETED THERAPY 9.1(2024):17.

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来源：上海药物研究所

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