Overview of monoclonal antibodies and small molecules targeting the epidermal growth factor receptor pathway in colorectal cancer.
The epidermal growth factor receptor (EGFR) provides survival signals and is overexpressed in the majority of colorectal cancers. As more is learned about the molecular details of EGFR signaling, antibodies can be designed to interfere with specific domains of the EGFR molecule. In this review, we analyze preclinical and current clinical data on EGFR-targeting molecules and their potential role in the treatment of colorectal cancer. Cetuximab binds to domain III of EGFR and hinders ligand binding. It is now approved by the US Food and Drug Administration for metastatic colorectal cancer treatment. Panitumumab is another widely studied anti-EGFR antibody with similar properties. Bispecific antibodies are modified immunoglobulin molecules containing 2 different binding specificities. These antibodies can redirect the immune response against tumor cells by tethering effector cells such as CD3e-expressing T cells or CD16-expressing natural killer cells and granulocytes to the surface of cancer cells. Tyrosine kinase inhibitors are quinazoline-derived, low molecular weight synthetic molecules that can block the intracellular tyrosine kinase domain of several receptors, including EGFR, Erb2, and vascular endothelial growth factor receptor, and thereby inhibit ligand-induced receptor phosphorylation and abrogate the biologic effect of EGFR signaling. The presence of skin rash and EGFR gene amplification have been advanced as possible predictors of clinical effectiveness of targeted anti-EGFR therapies.
Snyder
Lorraine C
LC
Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2412, USA.
Astsaturov
Igor
I
Weiner
Louis M
LM
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001665:Binding Sites; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000503:physiopathology*; D017277:Drug Approval; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D005076:Exanthema / Q000139:chemically induced; D005784:Gene Amplification; D006801:Humans; D008024:Ligands; D000077544:Panitumumab; D011379:Prognosis; D017452:Receptors, IgG / Q000096:biosynthesis; D015398:Signal Transduction; D014481:United States; D014486:United States Food and Drug Administration
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008024:Ligands; D017452:Receptors, IgG; D000077544:Panitumumab; D066246:ErbB Receptors; D000068818:Cetuximab