Beyond EGFR inhibition in head and neck squamous cell carcinoma: Overcoming resistance mechanisms and novel therapeutic frontiers

: Head and neck squamous cell carcinoma (HNSCC) remains a significant global health challenge. The epidermal growth factor receptor (EGFR) is overexpressed in the majority of HNSCCs and represents a well-established therapeutic target. Cetuximab, a chimeric IgG1 monoclonal antibody anti-EGFR, is the only EGFR-targeted agent approved for HNSCC and has shown efficacy in both locally advanced (in platinum-unfit patients) and recurrent/metastatic (R/M) settings. However, clinical benefit is limited by intrinsic and acquired resistance mechanisms, including EGFR mutations, compensatory activation of alternative receptor tyrosine kinases (RTKs), downstream pathway alterations (e.g., PIK3CA mutations, PTEN loss), epithelial-mesenchymal transition (EMT), and immunosuppressive tumor microenvironment factors. Emerging strategies aim to overcome resistance through dual EGFR inhibition, combination with new generation targeted agents, and immunomodulation. Irreversible pan-HER tyrosine kinase inhibitors (e.g., afatinib, dacomitinib), dual-target bispecific antibodies such as duligotuzumab (EGFR/HER3), petosemtamab (EGFR/LGR5) or ficerafusp alfa (EGFR/TGF-β) have led to promising preclinical and early-phase clinical activity. Additionally, intratumoral EGFR antisense DNA (EGFR-AS) has shown synergy with cetuximab and radiotherapy in preclinical models and a phase I trial. This narrative review provides a comprehensive overview of the EGFR signaling network in HNSCC, the mechanisms underpinning resistance to EGFR-targeted therapies, and the evolving therapeutic landscape. While EGFR remains a valid therapeutic target, future efforts must focus on biomarker-driven patient selection and combination strategies to enhance efficacy and durability of response. Ongoing trials will further define the role of emerging anti-EGFR agents and their integration into HNSCC treatment algorithms.