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The epidermal growth factor receptor (EGFR, ErbB-1, HER-1) is overexpressed in many epithelial tumors, particularly head and neck squamous cell carcinomas (HNSCCs) and is related to poor prognosis. For non-small cell lung cancer (NSCLC) it was found that activating mutations in the kinase domain of the receptor predicted a high response-rate to EGFR-specific kinase inhibitors. The goal of the present study was to investigate potential sequence changes of EGFR in HNSCC cells and to determine their possible role in tumor biology. The whole EGFR coding sequence of eleven previously well-characterized HNSCC cell lines was determined by RT-PCR sequencing. The response of the cells to the kinase inhibitor AG1478 and the monoclonal anti-EGFR antibody cetuximab was evaluated by cell cycle and Western blot analysis. None of the cell lines exhibited EGFR mutations. However, 4 out of the 11 (36%) cell lines harboured the K497 polymorphism in the receptor. The K497 cells appeared on average to be more sensitive to inhibitor treatment. This effect was particularly pronounced in the AG1478-treated tumor cells and was associated with the level of extracellular-signal regulated kinase-1/2 phosphorylation which appeared more efficiently inhibited in the cell lines exhibiting the K497 EGFR polymorphism. EGFR mutations are a rare event in HNSCC cell lines and, consistent with previous studies the EGFR codon 497 polymorphism could play a significant role in HNSCC disease and therapy response.