Hereditas · 2026
TLE1 as a key regulator of osimertinib resistance and EMT in lung adenocarcinoma: implications for prognosis and immunotherapy response.
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Chen Na, Wang Tianlin, Li Yi, Zhang Ruixia, Wei Xiduan, Wang Zhenglu
Аннотация
BACKGROUND: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) poses a considerable challenge for the long-term treatment of non-small cell lung cancer (NSCLC). This study aims to identify a novel biomarker associated with osimertinib resistance and explore its role in EGFR-TKI resistance in lung adenocarcinoma (LUAD).
METHODS: Comprehensive bioinformatics analysis were done using transcriptomic data from the TCGA and GEO databases to identify genes associated with osimertinib tolerance. Candidate genes were further screened against a histone modification-related gene set from MSigDB, leading to the identification of TLE1. The hub gene, TLE1, was further evaluated through survival analysis, GSEA and CIBERSORT analyses. Loss-of-function experiments performed in vitro were utilized to assess the impact of TLE1 on osimertinib resistance in LUAD.
RESULTS: TLE1 was of particularly noteworthy, exhibiting elevated expression in LUAD, especially in stage IV patients, and was associated with poor prognosis. GSEA results showed that mTOR, VEGF and HIF-1 signaling pathways were notably activated in the high TLE1 expression group. CIBERSORT analysis markedly elevated levels of regulatory T cells (Tregs) in the TLE1 high expression group. Additionally, epithelial-mesenchymal transition (EMT) scores were significantly elevated in osimertinib tolerant groups and exhibited a positive correlation with TLE1 expression. Furthermore, TLE1 expression was significantly higher in osimertinib-resistant PC9 cells compared to parental PC9 cells. Downregulation of TLE1 enhanced the sensitivity of osimertinib-resistant PC9 cells to osimertinib.
CONCLUSIONS: TLE1 was identified as a critical gene associated with osimertinib tolerance, influencing LUAD progression, potentially serving as a novel therapeutic target.
CLINICAL TRIAL NUMBER: Not applicable.
METHODS: Comprehensive bioinformatics analysis were done using transcriptomic data from the TCGA and GEO databases to identify genes associated with osimertinib tolerance. Candidate genes were further screened against a histone modification-related gene set from MSigDB, leading to the identification of TLE1. The hub gene, TLE1, was further evaluated through survival analysis, GSEA and CIBERSORT analyses. Loss-of-function experiments performed in vitro were utilized to assess the impact of TLE1 on osimertinib resistance in LUAD.
RESULTS: TLE1 was of particularly noteworthy, exhibiting elevated expression in LUAD, especially in stage IV patients, and was associated with poor prognosis. GSEA results showed that mTOR, VEGF and HIF-1 signaling pathways were notably activated in the high TLE1 expression group. CIBERSORT analysis markedly elevated levels of regulatory T cells (Tregs) in the TLE1 high expression group. Additionally, epithelial-mesenchymal transition (EMT) scores were significantly elevated in osimertinib tolerant groups and exhibited a positive correlation with TLE1 expression. Furthermore, TLE1 expression was significantly higher in osimertinib-resistant PC9 cells compared to parental PC9 cells. Downregulation of TLE1 enhanced the sensitivity of osimertinib-resistant PC9 cells to osimertinib.
CONCLUSIONS: TLE1 was identified as a critical gene associated with osimertinib tolerance, influencing LUAD progression, potentially serving as a novel therapeutic target.
CLINICAL TRIAL NUMBER: Not applicable.