Arteaga C L
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA.
J Clin Oncol. 2001 Sep 15;19(18 Suppl):32S-40S.
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.
大约二十年前，表皮生长因子受体（EGFR）被发现是突变的、组成型激活的致癌性v-erbB酪氨酸激酶的原癌基因，该激酶可诱导禽类成红细胞增多症。与突变的癌基因不同，EGFR需要通过配体与其细胞外（EC）结构域结合来激活，而其细胞效应则取决于其细胞质酪氨酸激酶的激活。EGFR及其配体在几种人类癌症中的过度表达以及它们与肿瘤进展加速的关联，为采用肿瘤选择性策略靶向该网络提供了理论依据。本文将讨论两种基于EGFR已知结构和功能的抗受体方法。第一种策略涉及开发针对受体非保守EC结构域的人源化单克隆抗体。这些抗体可阻断配体结合，并能诱导受体内吞和下调。第二种方法是生成ATP模拟物，它们与ATP竞争结合受体的激酶口袋，从而使信号转导失活。临床前和早期临床研究已经表明，这两种方法单独使用或与标准抗癌疗法联合使用，都将能够改变EGFR表达型癌症的自然病程，且对荷瘤宿主几乎没有毒性。
