Why the epidermal growth factor receptor? The rationale for cancer therapy.

There is a need for new, selective anticancer agents that differentiate between malignant and nonmalignant cells. The benefits of such agents would include a higher therapeutic index and lower toxicity than conventional therapies. Although expressed in nonmalignant cells, the epidermal growth factor receptor (EGFR) is highly expressed in a variety of tumors, and its expression correlates with poor response to treatment, disease progression, and poor survival. Evidence for a role for the EGFR in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor. Activation of the EGFR signaling pathway in cancer cells has been linked with increased cell proliferation, angiogenesis, and metastasis, and decreased apoptosis. Preclinical data show that anti-EGFR therapies can inhibit these effects in vitro and in vivo. In addition, preclinical data confirm that many such agents have the potential to increase the effectiveness of current cytotoxic agents. Following accelerated drug development programs, phase III trials are now under way for a number of EGFR-targeted therapies, including the monoclonal antibody IMC-C225 and the EGFR-tyrosine kinase inhibitors ZD1839 (Iressa) and OSI-774. Thus, the rationale for EGFR-targeted approaches to cancer treatment is apparent and now well established, and there is increasing evidence that they may represent a significant contribution to cancer therapy.