文章：

ERBB受体与癌症：靶向抑制剂的复杂性

ERBB receptors and cancer: the complexity of targeted inhibitors

原文发布日期：2005-05-01

DOI: 10.1038/nrc1609

类型: Review Article

开放获取: 否

要点：

1. The family of ERBB or epidermal growth factor (EGF) receptors includes four members: EGFR/ERBB1, ERBB2, ERBB3 and ERBB4. EGFR and ERBB2 are involved in development of numerous types of human cancer and they have been intensely pursued as therapeutic targets.
2. Two important types of ERBB inhibitor are in clinical use: humanized antibodies directed against the extracellular domain of EGFR or ERBB2, and small-molecule tyrosine-kinase inhibitors (TKIs) that compete with ATP in the tyrosine-kinase domain of the receptor.
3. In preclinical models, treatment of tumour cells with ERBB-directed TKIs and antibodies rapidly downregulates phosphatidylinositol-3-kinase–AKT, mitogen-activated protein kinase, SRC, and signal transducer and activator of transcription (STAT) signalling, and blocks the proliferation of tumour cells. In the clinic, skin biopsies (surrogate tissue), and to a limited extent tumours, have been analysed for the molecular consequences of treatment with ERBB inhibitors.
4. ERBB-directed therapeutics have demonstrated clinical efficacy; however, the antitumour effects are often not as strong as predicted from preclinical studies. There are likely to be various reasons why this is so, an important one being that other tumour-cell alterations influence the tumour response to ERBB-targeted inhibitors. Therefore, rational drug-combination strategies have great potential to combat the complexity of tumour biology.

要点翻译：

1. ERBB（又称表皮生长因子EGF）受体家族包含四个成员：EGFR/ERBB1、ERBB2、ERBB3和ERBB4。其中EGFR与ERBB2参与多种人类癌症的发生发展，因此已成为重要的治疗靶点。
2. 临床应用的ERBB抑制剂主要有两类：针对EGFR或ERBB2胞外结构域的人源化抗体，以及与受体酪氨酸激酶结构域ATP结合位点竞争性结合的小分子酪氨酸激酶抑制剂（TKIs）。
3. 在临床前模型中，使用ERBB靶向TKIs和抗体治疗肿瘤细胞可快速下调磷脂酰肌醇3-激酶-AKT、丝裂原活化蛋白激酶、SRC及信号转导与转录激活因子（STAT）信号通路，并阻断肿瘤细胞增殖。在临床实践中，通过皮肤活检（替代组织）及少量肿瘤组织样本，已对ERBB抑制剂治疗的分子效应进行了分析。
4. ERBB靶向治疗已展现临床疗效，但其抗肿瘤效果通常未达临床前研究的预期强度。这一现象可能涉及多种因素，重要原因之一在于其他肿瘤细胞变异会影响对ERBB靶向抑制剂的治疗反应。因此，合理的药物联合策略对于应对肿瘤生物学的复杂性具有巨大潜力。

英文摘要：

ERBB receptor tyrosine kinases have important roles in human cancer. In particular, the expression or activation of epidermal growth factor receptor and ERBB2 are altered in many epithelial tumours, and clinical studies indicate that they have important roles in tumour aetiology and progression. Accordingly, these receptors have been intensely studied to understand their importance in cancer biology and as therapeutic targets, and many ERBB inhibitors are now used in the clinic. We will discuss the significance of these receptors as clinical targets, in particular the molecular mechanisms underlying response.

摘要翻译： 

ERBB受体酪氨酸激酶在人类癌症中具有重要作用。特别是，表皮生长因子受体（EGFR）和ERBB2的表达或激活在多种上皮性肿瘤中发生改变，临床研究指出它们在肿瘤的病因学和进展中起关键作用。因此，这些受体被广泛研究以了解其在癌症生物学中的重要性，并作为治疗靶点，目前已有多种ERBB抑制剂应用于临床。我们将讨论这些受体作为临床靶点的重要性，尤其是其分子机制对治疗反应的影响。

原文链接：

ERBB receptors and cancer: the complexity of targeted inhibitors