Epidermal Growth Factor Receptor: Pathway, Therapies, and Pipeline

Background: The epidermal growth factor receptor (EGFR) pathway is important in tumor growth, survival, and metastasis and is now the target of several therapeutic agents. Objectives: This paper seeks to review the EGFR pathway, the study and use of EGFR-directed agents in non small-cell lung cancer (NSCLC) and colorectal cancer (CRC), and related new drug development. Methods: PubMed was searched for English-language articles by MeSH and title terms of EGFR published from 2006 to 2013, using the limits of clinical trials as well as reviews. Reference lists were assessed for relevant articles, and guidelines were searched. Clinicaltrials.gov and meeting abstracts were queried for investigational agents. Eligible papers included those concerning EGFR biology, NSCLC or CRC studies involving EGFR-directed agents, and/or investigational drugs targeting EGFR and/or associated pathways. Results: The activity of oral tyrosine kinase inhibitors (TKIs) against EGFR has improved survival in NSCLC, and these agents particularly effective in cancers with an EGFR mutation. Resistance to TKIs is most commonly related to a second, T790M, mutation, or to MET amplification, with newer agents directed against these mechanisms. Conversely, in CRC, TKIs have been ineffective, whereas monoclonal antibodies have improved survival. Both primary and secondary KRAS mutations in CRC abrogate mAb effectiveness. Several targets, including MET, BRAF, and PI3K, may serve useful in combination with anti-EGFR drugs. Conclusions: Exploitation of EGFR-directed therapies has offered improvement in survival and quality of life in NSCLC and CRC. New therapies directed at EGFR may offer further improvements. However, resistance mechanisms suggest that combination therapies or multitargeted agents will be crucial in making significant future advances. (C) 2013 Elsevier HS Journals, Inc. All rights reserved.