Abstract
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, with epidermal growth factor receptor (EGFR) mutations being a common driver. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), has shown efficacy in treating NSCLC patients harboring EGFR mutations. However, resistance to osimertinib poses a significant clinical challenge. This study aims to identify key genes associated with osimertinib resistance in NSCLC and elucidate their underlying mechanisms to inform new therapeutic strategies. Utilizing a comprehensive bioinformatics approach, we conducted differential expression analysis, enrichment analysis, consensus clustering, drug sensitivity analysis, protein-protein interaction (PPI) network construction, and immune infiltration analysis. Our findings revealed 126 genes, including KRT14, KRT16, KRT17, KRT5, KRT6A, KRT6B, TP63, and TRIM29, that are potentially pivotal in osimertinib resistance. Enrichment analyses indicated significant involvement in biological processes such as epidermis development and keratinocyte differentiation, and pathways like valine, leucine, and isoleucine degradation. Immune infiltration analysis showed significant downregulation of 14 immune cell types in the resistant group, with notable negative correlations between hub genes and specific immune cells. We constructed a diagnostic model with an area under the curve (AUC) greater than 0.9,,validated externally, demonstrating robust diagnostic performance. Interaction networks, including mRNA-TF, RBP-mRNA, and lncRNA-miRNA-mRNA, provided insights into the complex regulatory mechanisms of resistance.