The epidermal growth factor receptor: From mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia

被引:0
|
作者
Arteaga, CL
机构
[1] Vanderbilt Univ, Sch Med, Div Hematol Oncol, Dept Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA
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中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Oncology.Approximately two decades ago, the epidermal growth factor receptor (EGFR) was discovered to be the proto-oncogene of the mutant, constitutively active oncogenic v-erbB tyrosine kinase, which induces avian erythroblastosis. Unlike the mutant oncogene, the EGFR requires activation by binding of ligand to its extracellular (EC) domain, whereas its cellular effects depend on activation of its cytoplasmic tyrosine kinase. The overexpression of EGFR and its ligands in several human carcinomas and their association with accelerated tumor progression provided a rationale for targeting this network with tumor-selective strategies. Two of those antireceptor approaches, both solidly based on the known structure and function of the EGFR, are discussed. The first strategy involves the development of humanized monoclonal antibodies against the nonconserved receptor's EC domain. These antibodies block ligand binding and can induce receptor endocytosis and downregulation. The second approach is the generation of ATP mimetics that compete with ATP for binding to the receptor's kinase pocket, thus disabling signal transduction. Preclinical and early clinical studies already suggest that both of these approaches, either alone or in combination with standard anticancer therapies, will be able to alter the natural history of EGFR-expressing cancers with little to no toxicity to the tumor-bearing host. (C) 2001 by American Society of Clinical Oncology.
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页码:32S / 40S
页数:9
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