ArticleSignal transduction and targeted therapy2024
Branched-chain amino acid transaminase 1 confers EGFR-TKI resistance through epigenetic glycolytic activation.
Article in Signal transduction and targeted therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.Signal transduction and targeted therapy · 2026Review
- Opportunities and challenges in the development of evolving EGFR inhibitors to overcome EGFR TKIs resistance.Acta pharmacologica Sinica · 2026Review
- Suppression of UCP2 alleviates leukemogenesis by enhancing branched-chain amino acids-induced oxidative stress via activating the PI3K/AKT/mTOR signaling pathway.Genes & diseases · 2026Article
- Nuclear PD-L1: an emerging oncogenic driver and promising therapeutic target in cancer.Journal of biomedical science · 2026Review
- BCAT1 inhibits crotonate-related epigenetic modulation of metabolic genes in tumor-associated macrophages to counter immunosuppression.Nature communications · 2026Article
- Dietary intake and BCAA metabolism regulate pulmonary fibrosis through KDM4A-mediated epigenetic remodeling in male mice.Nature communications · 2026Article
- Review
- USP7-dependent stabilization of FKBP4 contributes to acquired osimertinib resistance through glycolytic remodeling in NSCLC.Scientific reports · 2026Article
- Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance.The Journal of clinical investigation · 2026Article
- Multi-omics integration in deciphering non-small cell lung cancer drug resistance: current status, challenges, and future prospects.Hereditas · 2026Review
- Atlas-Guided Nanocarrier Strategies Targeting Spatial NTRK2/MAPK Signaling in EGFR-TKI-Resistant Niches of Esophageal Squamous Cell Carcinoma.Pharmaceutics · 2026Review
- DRESIS 2.0: the comprehensive landscape of drug resistance information.Nucleic acids research · 2026Article
- Branched-chain amino acid transaminases as promising targets in tumor therapy.Frontiers in cell and developmental biology · 2026Review
- BCAAs and related metabolic enzymes: partners in crime driving tumor development.Frontiers in cell and developmental biology · 2026Review
- Immunometabolism: crosstalk with tumor metabolism and implications for cancer immunotherapy.Molecular cancer · 2025Review
- Review
- Targeting AKR1B1 inhibits metabolic reprogramming to reverse systemic therapy resistance in hepatocellular carcinoma.Signal transduction and targeted therapy · 2025Article
- Metabolic hallmarks of trastuzumab resistance.Expert opinion on therapeutic targets · 2025Review
- BCAT1 Activation Reprograms Branched-Chain Amino Acid Metabolism and Epigenetically Promotes Inflammation in Diabetic Retinopathy.Investigative ophthalmology & visual science · 2025Article
- Unveiling the Maze: Branched-Chain Amino Acids Fueling the Dynamics of Cancer Metabolism and Progression.Cancers · 2025Review
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28 authors.
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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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