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Recent insights in the PI3K/Akt pathway as a promising therapeutic target in combination with EGFR-targeting agents to treat head and neck squamous cell carcinoma. The Epidermal Growth Factor Receptor (EGFR) is overexpressed in the majority of Head and Neck Squamous Cell Carcinomas (HNSCC). This triggered the development of multiple anti-EGFR agents as a potential treatment strategy for this disease. Despite initial promising results and clinical implementation of one of the first successfully approved targeted therapies in solid tumor treatment, namely the EGFR-specific antibody cetuximab, intrinsic and acquired resistance often occurs with a negative effect on outcome.