CAF‐secreted COL5A2 activates the PI3K/AKT pathway to mediate erlotinib resistance in head and neck squamous cell carcinoma

Abstract Objective To investigate the mechanisms behind acquired resistance to erlotinib in head and neck squamous cell carcinoma (HNSCC) with a focus on the role of cancer‐associated fibroblasts (CAFs) and the PI3K/AKT signaling pathway. Materials and Methods This study analyzed gene expression profiles of erlotinib‐sensitive and ‐resistant HNSCC cell lines using datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. It included microarray and RNA‐sequencing data, differentially expressed genes (DEGs) analysis, and pathway enrichment. In vitro experiments assessed the functional role of CAFs and the impact of the extracellular matrix component COL5A2 on erlotinib resistance. Results We identified 124 DEGs associated with erlotinib resistance, with key genes like COL5A2 significantly upregulated. CAFs were found to highly express COL5A2, enhancing erlotinib resistance by activating the PI3K/AKT pathway. Higher erlotinib resistance scores correlated with increased infiltration of CAFs. Conclusions Erlotinib resistance in HNSCC is significantly influenced by the tumor microenvironment (TME), particularly through CAFs and the PI3K/AKT pathway. Targeting these mechanisms may offer new therapeutic strategies to overcome resistance in HNSCC patients.