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.


OBJECTIVE
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.
Department of Oncology, Faculty of Health Sciences, McMaster University, Hamilton, Canada. Electronic address: goffin@mcmaster.ca.
John R
JR
Goffin
Kevin
K
Zbuk
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015507:Drugs, Investigational; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors
colorectal cancer; epidermal growth factor receptor; investigational new drugs; non–small cell lung cancer