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Branched-chain amino acid transaminase 1 confers EGFRTKI resistance through epigenetic glycolytic activation
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作者 Tao Zhang Zilu Pan +25 位作者 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 《Signal Transduction and Targeted Therapy》 SCIE CSCD 2024年第9期4103-4119,共17页
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 AS... 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. 展开更多
关键词 METABOLISM IMPAIRED RESISTANCE
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A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy
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作者 Yingqiang liu Linjiang Tong +11 位作者 Mengge Zhang Qi Zhang qiupei liu Fang Feng Yan Li Mengzhen Lai Haotian Tang Yi Chen Meiyu Geng Wenhu Duan Jian Ding Hua Xie 《Cancer Communications》 SCIE 2024年第3期438-442,共5页
Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor... Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug resistance.The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors. 展开更多
关键词 alterations KRAS SARCOMA
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