Resistance to EGFR inhibitors: Molecular determinants and the enigma of head and neck cancer

The epidermal growth factor receptor (EGFR or ERBB1), is aberrantly activated in many human malignancies , including colorectal cancer, non-small cell lung cancer, and head and neck squamous cell carcinoma (HNSCC). In these diseases, overexpression correlates with poor survival. Inhibitors of EGFR signaling, both monoclonal antibodies (cetuximab, panitumumab) and tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib), demonstrate activity in these cancers, but responses are heterogeneous. Resistance to EGFR-inhibiting agents continues to pose a substantial obstacle to their effective use. Many tumors do not initially respond, indicative of intrinsic resistance; of those responding, most eventually progress, demonstrating acquired resistance. In the treatment of HNSCC, cetuximab, in combination with radiation therapy, achieves substantial rates of response[1]. However, the response rate to single-agent cetuximab is only 10-15%; to erlotinib, 5%[2, 3]. Molecular predictors of response to EGFR inhibition in HNSCC remain poorly defined.