From the Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
Author's disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Mark A. Socinski, MD, Director, the Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, 3006 Old Clinic Blvd, CB #7395, Chapel Hill, NC 27599-7295; e-mail: socinski{at}med.unc.edu
Overview: The epidermal growth factor receptor (EGFR) is expressed in the majority of non-small cell lung cancers (NSCLCs) and belongs to the HER family of cell membrane receptors.1 The major ligands for the EGFR are epidermal growth factor and transforming growth factor-alpha that bind to the extracellular domain, resulting in receptor dimerization and autophosphorylation of the intracellular tyrosine kinase domain. This event leads to downstream signaling via the ras, raf, mitogen-activated protein kinase, phosphatidyl-3-kinase, and ERK1/ERK2 pathways linking the extracellular ligand-binding event to cell growth, proliferation, invasion, and survival.1 As EGFR is expressed and, to some degree, involved in the pathogenesis of most cases of NSCLC, targeting of this pathway has been the focus of clinical trials for over a decade. To date, the major therapeutic approaches to EGFR have been the use of either monoclonal antibodies targeting the extracellular domain or small molecule tyrosine kinase inhibitors (TKIs) that target the intracellular TK domain. Agents in both classes of anti-EGFR drugs have been tested in many phase III trials in advanced NSCLC, either alone or in combination with various chemotherapeutic agents with varying results.2 Because this is a cell membrane receptor, much research has been focused on the presence and dominance of the "target" pathway (EGFR) and the appropriate way in which to identify patients who will receive greater therapeutic benefit from these agents. The discovery of activating EGFR mutations,3,4 which confer great sensitivity to EGFR TKIs, was a major step forward in understanding the biology of this pathway.
