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

作　　者：Tao Zhang Zilu Pan Jing Gao Qingqing Wu Gang Bai Yan Li Linjiang Tong Fang Feng Mengzhen Lai Yingqiang Liu Peiran Song Yi Ning Haotian Tang Wen Luo Yi Chen Yan Fang Hui Zhang Qiupei Liu Yudi Zhang Hua Wang Zhiwei Chen Yi Chen Meiyu Geng Hongbin Ji Guilong Zhao Hu Zhou Jian Ding Hua Xie 

机构地区：[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

出　　处：《Signal Transduction and Targeted Therapy》2024年第9期4103-4119,共17页信号转导与靶向治疗（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(82273948 and 81903638);High-level Innovative Research Institute(2021B0909050003);State Key Laboratory of Drug Research(SKLDR-2023-TT-01 and SIMM2205KF-09);Lingang Laboratory(LG202103-02-02);Institutes for Drug Discovery and Development,Chinese Academy of Sciences(CASIMM0120225003-1 and-2);Guangdong Basic and Applied Basic Research Foundation(2021A1515010197 and 2023A1515012259);Zhongshan Municipal Natural Science Foundation(200805173640573 and 210730214049987);Project of Shanghai Institute of Materia Medica,Chinese Academy of Sciences(SIMM0120231001).

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(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.

关 键 词：METABOLISM IMPAIRED RESISTANCE 

分 类 号：R734.2[医药卫生—肿瘤] R96[医药卫生—临床医学]