Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs
Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs
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DOI：
10.1158/1078-0432.ccr-06-0646
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发表时间：
2006-12-15
影响因子：
11.5
通讯作者：
Kuwano, Michihiko
中科院分区：
文献类型：
--
作者：
Ono, Mayumi;Kuwano, Michihiko
表皮生长因子受体（EGFR）家族的受体酪氨酸激酶，包括EGFR、HER 2/erbB 2和HER 3/erbB 3，是抗肿瘤策略的有吸引力的靶点。异常EGFR信号传导与各种恶性肿瘤的进展相关，并且在对EGFR靶向小分子药物（如吉非替尼和厄洛替尼）有反应的非小细胞肺癌患者中已发现EGFR基因中的体细胞酪氨酸激酶结构域突变。EGFR过表达被认为是各种恶性肿瘤中激活的主要机制。此外，EGFR拷贝数增加与非小细胞肺癌患者生存期改善相关，表明突变型和/或野生型EGFR分子表达增加可能是吉非替尼反应的分子决定因素。然而，由于EGFR突变和/或基因增益并没有在所有对治疗有部分应答的患者中观察到，因此替代机制可能会赋予EGFR靶向药物敏感性。临床前研究表明，对EGFR酪氨酸激酶抑制剂的敏感性取决于每种癌症中细胞存活和生长信号与EGFR以及HER 2和HER 3的耦合程度。这篇综述还描述了EGFR磷酸化和药物敏感性之间的可能关联，以及讨论吉非替尼与EGFR激活和磷脂酰肌醇3-激酶/Akt激活血管内皮细胞的抗血管生成作用。
The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, including EGFR, HER2/erbB2, and HER3/erbB3, is an attractive target for antitumor strategies. Aberrant EGFR signaling is correlated with progression of various malignancies, and somatic tyrosine kinase domain mutations in the EGFR gene have been discovered in patients with non-small cell lung cancer responding to EGFR-targeting small molecular agents, such as gefitinib and erlotinib. EGFR overexpression is thought to be the principal mechanism of activation in various malignant tumors. Moreover, an increased EGFR copy number is associated with improved survival in non-small cell lung cancer patients, suggesting that increased expression of mutant and/or wild-type EGFR molecules could be molecular determinants of responses to gefitinib. However, as EGFR mutations and/or gene gains are not observed in all patients who respond partially to treatment, alternative mechanisms might confer sensitivity to EGFR-targeting agents. Preclinical studies showed that sensitivity to EGFR tyrosine kinase inhibitors depends on how closely cell survival and growth signalings are coupled with EGFR, and also with HER2 and HER3, in each cancer. This review also describes a possible association between EGFR phosphorylation and drug sensitivity in cancer cells, as well as discussing the antiangiogenic effect of gefitinib in association with EGFR activation and phosphatidylinositol 3-kinase/Akt activation in vascular endothelial cells.