Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia☆,☆☆,★
Section snippets
Signal transduction by the epidermal growth factor receptor network
THE EPIDERMAL growth factor receptor (EGFR) (also known as HER1 or erbB1) is a ubiquitous 170-kd membrane-spanning glycoprotein composed of an amino-terminal extracellular (EC) ligand-binding domain, a hydrophobic single transmembrane helix, a cytoplasmic domain containing the tyrosine kinase domain, and a carboxy-terminal region containing critical tyrosine residues and receptor regulatory motifs.1 Binding of a specific set of ligands (EGF, transforming growth factor-alpha [TGF-α],
Role of epidermal growth factor receptor signaling in transformation and tumor progression
Signaling by the EGFR and the erbB receptor network serves a crucial role in epithelial development, proliferation, and organogenesis. Oncogenic activation of this pathway occurs as a result of EGFR mutation, overexpression, structural rearrangements, and/or relief of its normal autoinhibitory and regulatory constraints. Mutations of the EGFR, like that encoded by v-erbB, are most common in nonhuman neoplasias.5 Transfection of high levels of EGFR and its ligand, TGF-α, has been shown to induce
Rationale in support of the epidermal growth factor receptor network as a therapeutic target
The coexpression of EGFR and ligands at tumor sites allows for EGFR activation via autocrine/paracrine mechanisms. In support of the operational nature of these signaling pathways in EGFR-expressing tumor cells, interruption of signaling with various EGFR inhibitors has been shown to inhibit tumor cell proliferation and/or viability both in vitro and in vivo.28, 29 These observations coupled with (1) the ability to identify EGFR-expressing human tumors in diagnostic tissue from patients, (2)
Molecular strategies to block epidermal growth factor receptor function: Receptor antibodies
One antireceptor strategy has been the use of monoclonal antibodies that recognize the receptor's ectodomain, compete for ligand binding, and induce EGFR dimerization and downregulation from the cell surface (Fig 2).
Low-molecular-weight epidermal growth factor receptor tyrosine kinase inhibitors
A second antisignaling strategy was based on the observation that mutations in the adenosine triphosphate (ATP)-binding pocket of the EGFR (Fig 2) severely affect its tyrosine kinase function30 and the ability of the EGFR to transform cells. This strategy has involved the random screening of small molecules that compete for the Mg-ATP binding site of the catalytic domain of the EGFR tyrosine kinase from natural or synthetic compound libraries.45 Table 1 shows a list of the EGFR tyrosine kinase
Conclusions
It was less than 20 years ago when it was discovered that the EGFR is the cellular proto-oncogene of a mutant EGFR that induces avian erythroblastosis. The high levels of EGFR and its ligands in several common human carcinomas led to drug discovery and preclinical studies that supported the use of this signaling network as a target for novel treatment approaches. Many questions about the clinical development of these strategies remain unanswered. Of particular importance are the issue of tests
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Supported in part by National Institutes of Health grant no. R01 CA80195, the Susan G. Komen Breast Cancer Foundation, and Vanderbilt-Ingram Cancer Center support grant no. CA68485.
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Dr Arteaga has received research grant support from Genentech BioOncology. He has served as a consultant to and received honoraria from AstraZeneca and Genentech BioOncology.
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Address reprint requests to Carlos L. Arteaga, MD, Division of Hematology-Oncology, Vanderbilt University School of Medicine, 2220 Pierce Ave, 777 Preston Research Bldg, Nashville, TN 37232-6307.