Targeting the EGFR in neoplasia—more questions than answers

Forty years ago, the study of retroviral transformation revolutionized our understanding of malignant transformation. The discovery of virally transmitted oncogenes was closely followed by the realization that they were homologues of mammalian genes, thus leading to the term proto-oncogenes. The epidermal growth factor receptor (EGFR; HER1; erbB1) is a prominent example for this sequence of events. First cloned in 1984, it was immediately recognized to be the counterpart of a viral oncogene, v-erbB (1). In keeping with its oncogenic potential, the EGFR is molecularly altered and deregulated in many “spontaneous” tumors with no apparent viral etiology. The EGFR is one of many receptor tyrosine kinases with transforming potential. Yet, it is believed to contribute to the malignant phenotype of a broad spectrum of neoplasms affecting primarily epithelial tissues. Almost 20 years after its discovery, the EGFR has emerged as a prominent target for therapeutic intervention. This supplement to the International Journal of Radiation Oncology, Biology, Physics contains proceedings of the Radiation Therapy Oncology Group symposium “Epidermal Growth Factor Receptor Inhibitors and Cancer Therapeutics” held in Philadelphia in June 2002. It focuses on the preclinical development and clinical evaluation of EGFR antagonists. Meeting participants presented the epidemiologic rationale for targeting the EGFR, highlighted the complexity of signaling events downstream of EGFR activation and relevant to malignant transformation, and delineated strong preclinical evidence that the EGFR is a worthy therapeutic target. Most importantly, the meeting provided a forum to discuss functional roles of the EGFR as they relate to tumor development in vivo and emerging problems in the application of EGFR antagonists to clinical practice. EGFR expression and activation The EGFR is a widely expressed transmembrane protein composed of an extracellular ligand-binding domain, a hydrophobic transmembrane region, and a cytoplasmic domain with intrinsic tyrosine kinase activity, tyrosine residues, and regulatory motifs (2, 3). Activation of EGFR is elicited by the binding of at least 6 ligands, including epidermal growth factor (EGF), transforming growth factor(TGF), and amphiregulin, to its extracellular domain. Ligand binding triggers EGFR dimerization, activation, and autophosphorylation of several tyrosine residues in the carboxy-terminal region of the intracellular domain (4). Subsequently, intracellular substrates with Src-homology 2 and phosphotyrosine-binding domains bind to the phosphorylated tyrosine residues, leading to activation of multiple intracellular signaling pathways, and in turn, to cell proliferation, survival, differentiation, migration, and other cellular responses (Fig. 1) (2–4). In this supplement, Drs. Marmor and Yarden discuss signal transduction and oncogenesis by ErbB receptors. They outline an extraordinary complex system of signaling events triggered by EGFR activation, as well as the contribution of signaling networks at the cell surface capable of amplifying EGFR-dependent signals. The EGFR is expressed or overexpressed in a large number of malignancies, including non–small-cell lung (NSCLC), head-and-neck, esophageal, gastric, colorectal, breast, prostate, bladder, renal, pancreatic, and ovarian cancer (5, 6). EGFR expression is often found in association with increased expression of its ligands, EGF, TGF, or amphiregulin (2). Despite conflicting reports, EGFR expression is generally considered predictive of a poor prognosis, particularly in head-and-neck, ovarian, cervical, bladder, and esophageal cancer (7). Several articles presented here validate the functional relevance of EGFR expression in clinical oncology. Dr. Ang discusses an immunohistochemistry approach used to determine the prognostic significance