Revealing the Action Mechanism of the FOXA 2‐ LAMC 2 Axis in Driving Cisplatin Resistance of Head and Neck Squamous Cell Carcinoma via Based Multi‐Omic Analysis and Experimental Validation

Cisplatin is a key treatment for head and neck squamous cell carcinoma (HNSCC), but the development of resistance severely limits its effectiveness. The molecular determinants underlying cisplatin resistance in HNSCC remain unclear. Multiple databases were used to screen the core genes related to cisplatin resistance in HNSCC patients. Tumor tissue samples from HNSCC patients were collected and the expression of FOXA2 was verified through various pathological tests to establish the correlation between FOXA2 expression and the clinical characteristics of the patients. The in vitro and patient-derived organoids (PDOs) models were used to verify the regulatory effect of FOXA2 on the cisplatin resistance of HNSCC. Transcriptome sequencing combined with multi-omics analysis demonstrated that LAMC2 is a downstream target of FOXA2 in regulating cisplatin resistance. Bioinformatic screening of cisplatin-resistant cohorts revealed that FOXA2 was the only gene significantly associated with poor survival outcomes in TCGA-HNSCC patients. Transcriptomic profiling and pathway enrichment analyses revealed the activation of the PI3K/AKT signaling cascade. We identified LAMC2 as a direct transcriptional target of FOXA2. Chromatin immunoprecipitation and luciferase reporter assays confirmed FOXA2 binding to the LAMC2 promoter, resulting in transcriptional activation. FOXA2-mediated upregulation of LAMC2 increased PI3K and AKT phosphorylation, and LAMC2 overexpression reversed the impaired malignant phenotypes caused by FOXA2 silencing. In xenograft models and PDO systems, FOXA2 overexpression reduced responsiveness to cisplatin, whereas FOXA2 inhibition significantly increased therapeutic sensitivity. Our research has identified a previously unrecognized regulatory axis involving FOXA2, LAMC2, and PI3K/AKT, which plays a crucial role in the progression and resistance to cisplatin in HNSCC. Therefore, targeting the FOXA2-LAMC2 axis may represent a novel therapeutic strategy to overcome cisplatin resistance in HNSCC.