CAV2 Confers Cetuximab Resistance in HNSCC by Ubiquitin-Mediated Disruption of the PACT-PKR Tumor Suppressor Axis

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) frequently exhibits resistance to targeted therapies, including cetuximab. Identifying key drivers of tumor progression and elucidating the mechanisms underlying therapeutic resistance are essential for improving clinical outcomes. This study aimed to investigate the role of Caveolin-2 (CAV2) in HNSCC proliferation and cetuximab resistance. Methods: Prognosis-associated genes in HNSCC were screened using the TCGA database. The functional role of CAV2 in cell proliferation and apoptosis was assessed via CCK-8, colony formation, and flow cytometry assays. Mechanistic insights were obtained through co-immunoprecipitation, ubiquitination assays, and proteomic analysis. The impact of CAV2 on cetuximab sensitivity was evaluated both in vitro and in a xenograft mouse model. Results: CAV2 emerged as a top prognostic candidate. Knockdown of CAV2 significantly suppressed HNSCC cell proliferation and induced apoptosis. Mechanistically, CAV2 interacted with and stabilized the PACT protein, thereby inhibiting PKR activation via the ubiquitin–proteasome pathway. Notably, CAV2 deficiency markedly enhanced the sensitivity of HNSCC cells and tumor xenografts to cetuximab treatment. Conclusions: These findings establish CAV2 as a critical driver of HNSCC progression and cetuximab resistance through post-translational regulation of the PACT–PKR axis. Targeting CAV2 may therefore represent a promising strategy to potentiate the efficacy of EGFR-targeted therapy in HNSCC.