The epidermal growth factor receptor-tyrosine kinase: a promising therapeutic target in solid tumors

The overexpression and aberrant function of the epidermal growth factor receptor (EGFR) and its ligands in several human carcinomas have provided a rationale for targeting this signaling network with novel treatment approaches. The epidermal growth factor receptor-tyrosine kinase (EGFR-TK) is a selective target for inhibiting cancer because it is activated in many tumor cells, yet is strictly controlled in normal cells. The EGFR-TK initiates diverse signal transduction pathways in tumor cells that have a profound effect on their biology. Activation of the EGFR-TK provides signals that drive dysregulated proliferation, invasion and metastasis, angiogenesis, and enhanced cell survival. Therefore, the EGFR-TK is a promising drug target for many types of solid tumors, and its inhibition has potential in both the treatment and prevention of these neoplasias. Based on the structure and function of the EGFR, two antireceptor therapeutic strategies have been developed. The first strategy uses humanized monoclonal antibodies generated against the receptor's ligand-binding, extracellular domain. These antibodies block binding of receptor-activating ligands and, in some cases, can induce receptor endocytosis and downregulation. The second approach uses small molecules that compete with adenosine triphosphate for binding to the receptor's kinase pocket, thus blocking receptor activation and the transduction of postreceptor signals. Early clinical studies suggest that both of these approaches, either alone or in combination with standard anticancer therapies, are well tolerated and can induce clinical responses and tumor stabilization in a variety of common carcinomas. ZD1839 (Iressa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) is the EGFR-TK inhibitor furthest along in clinical development, and it is currently being investigated in a variety of solid tumors, including non-small-cell lung cancer.