Epidermal growth factor receptor dependence in human tumors: more than just expression?
Epidermal growth factor receptor dependence in human tumors: more than just expression?
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DOI：
10.1634/theoncologist.7-suppl_4-31
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发表时间：
2002-08
期刊：
影响因子：
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通讯作者：
C. Arteaga
中科院分区：
文献类型：
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作者：
C. Arteaga
表皮生长因子受体(EGFR)是抗肿瘤策略的合理靶点。EGFR信号可促进细胞增殖，减少细胞凋亡，增强肿瘤细胞的运动能力和新生血管生成。EGFR在多种上皮来源的人类肿瘤中均有表达或高表达。ZD1839(易瑞沙)是一种口服活性、选择性的EGFR酪氨酸激酶抑制剂，可阻断与癌细胞增殖和生存有关的信号转导途径。由于缺乏评估EGFR水平的一致方法，导致关于EGFR作为预后因素的报道存在差异；然而，对于一些肿瘤来说，EGFR是与更具侵袭性的疾病和更低的生存期相关的强烈预后指标。到目前为止，还没有发现EGFR水平和对EGFR靶向药物的反应之间的明确联系。ZD1839的临床前研究在某些情况下注意到了两者之间的关系，但在另一些情况下则没有。除了EGFR的高表达外，还可以通过多种机制增加EGFR信号，包括受体突变、与该受体家族其他成员的异源二聚化，如HER2(ErbB2)，(自分泌/旁分泌)配体的表达增加，以及控制受体信号输出的分子的变化。这些成分中的每一个都可以被评估以给出EGFR信号放大的大小的指示。对EGFR下游信号成分的评估应提供有关EGFR途径激活的信息。在基于EGFR的分析预测对受体靶向治疗的反应之前，没有明确的理由根据EGFR状态对患者进行分层，或将低EGFR水平的患者排除在使用ZD1839或其他EGFR抑制剂的试验之外。
The epidermal growth factor receptor (EGFR) is a rational target for antitumor strategies. EGFR signaling causes increased proliferation, decreased apoptosis, and enhanced tumor cell motility and neo-angiogenesis. The EGFR is expressed or highly expressed in a variety of human tumors of epithelial origin. ZD1839 (Iressa) is an orally active, selective EGFR tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. The lack of a consistent method of evaluating levels of EGFR has caused a disparity in reports of the EGFR as a prognostic factor; however, for some tumors, EGFR is a strong prognostic indicator associated with more aggressive disease and reduced survival. So far, no clear association between EGFR levels and response to EGFR-targeted agents has been found. Preclinical studies with ZD1839 have noted a relationship between the two in some cases, but not others. EGFR signaling may be increased by a number of mechanisms in addition to high expression levels of EGFR, including receptor mutations, heterodimerization with other members of this receptor family such as HER2 (erbB2), increased expression of (autocrine/ paracrine) ligands, and alterations in molecules that control receptor signaling output. Each of these components could be assessed to give an indication of the magnitude of EGFR signal amplification. Evaluation of signaling components downstream from EGFR should provide information on the activation of the EGFR pathway. Until EGFR-based assays predictive of a response to receptor-targeted therapies are available, there is no clear justification for stratifying patients by EGFR status or excluding patients with low EGFR levels from trials with ZD1839 or other EGFR inhibitors.