Abstract

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.