Head and neck squamous cell carcinoma (HNSCC) affects over half a million people worldwide. Despite advances in biology and medicine, only half of the patients are alive in 5 years. The epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of HNSCC cases, and it is correlated with poor responses to therapy and worse prognosis. Multiple therapies targeting this pathway have been tested. However, only a minority of patients has showed meaningful responses to these agents and almost all who do develop acquired tumor resistance after a few months of treatment. Recently, a significant interest has focused on identifying mechanisms of acquired and de novo resistance of EGFR blockage. In addition, other inhibitors of EGFR that interfere with known molecular pathways activated in HNSCC have been studied extensively, either as single agents or in combination with other treatment modalities. Here we review some of EGFR resistance mechanisms and briefly discuss new molecular therapeutic strategies to overcome that resistance in HNSCC.
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