文章：

新的抗癌靶点：重新审视ERBB2和发现ERBB3

Novel anticancer targets: revisiting ERBB2 and discovering ERBB3

原文发布日期：2009-06-18

DOI: 10.1038/nrc2656

类型: Review Article

开放获取: 否

要点：

1. The Erbb family consists of four closely related type 1 transmembrane tyrosine kinase receptors: the epidermal growth factor receptor (EGFR; also known as ERBB1), ERBB2, ERBB3 and ERBB4. Signalling through the Erbb family underpins many of the cellular activities on which cell survival and function depend.
2. EGFR, ERBB2 and ERBB3 are all implicated in the development and progression of cancer, and heterodimerization of the receptors plays a crucial part in their function. The role of ERBB4 in oncogenesis is less clear and this receptor might be involved in inhibition of cell growth rather than proliferation.
3. Aberrant ERBB2 expression or function has been implicated in the evolution of both breast and gastric cancers and is evident in other cancer types, including ovarian and salivary gland tumours. This receptor has proved to be a potent target for anticancer therapies, including antibody-based therapies to prevent ligand binding, dimer formation or antibody-dependent cell-mediated cytotoxicity, and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners.
4. New strategies against ERBB2 include Erbb tyrosine kinase inhibitors, heat shock protein 90 inhibitors, Erbb dimerization inhibitors and antibody–chemotherapy conjugates. All of these approaches have shown substantial clinical activity in patients who have progressed on trastuzumab, an anti-ERBB2 monoclonal antibody.
5. The extent of the role of ERBB3 is now emerging and considerable research efforts are focused on developing new therapies that target ERBB3.
6. ERBB3-specific monoclonal antibodies are now under evaluation, and data suggest that individual tyrosine kinase inhibitors might inhibit ERBB3 activation or its interaction with downstream signalling components.
7. Preventing the dimerization of ERBB3 with its signalling partners, in particular ERBB2 with which it forms the most potent mitogenic signalling dimer, might offer an effective method of preventing oncogenic signalling across the Erbb network.

要点翻译：

1. Erbb家族由四种密切相关的1型跨膜酪氨酸激酶受体组成：表皮生长因子受体（EGFR，亦称ERBB1）、ERBB2、ERBB3和ERBB4。通过Erbb家族传导的信号支撑着细胞生存与功能所依赖的多种细胞活动。
2. EGFR、ERBB2和ERBB3均参与癌症的发生与发展，其中受体的异二聚化在其功能中起关键作用。ERBB4在肿瘤发生中的作用尚不明确，该受体可能参与抑制细胞生长而非促进增殖。
3. ERBB2的异常表达或功能异常与乳腺癌和胃癌的演进相关，并在卵巢癌、唾液腺肿瘤等其他癌症类型中表现明显。该受体已被证实是抗癌治疗的重要靶点，相关策略包括：采用基于抗体的疗法阻断配体结合、二聚体形成或介导抗体依赖性细胞毒性，以及通过直接激酶抑制阻止分子激活与下游信号伙伴的募集。
4. 针对ERBB2的新策略包括Erbb酪氨酸激酶抑制剂、热休克蛋白90抑制剂、Erbb二聚化抑制剂以及抗体-化疗药物偶联物。所有这些方法在曲妥珠单抗（一种抗ERBB2单克隆抗体）治疗无效的患者中均显示出显著的临床活性。
5. ERBB3的作用范围正逐渐明晰，大量研究致力于开发靶向ERBB3的新疗法。
6. 目前正在评估ERBB3特异性单克隆抗体，数据显示特定酪氨酸激酶抑制剂可能抑制ERBB3激活或其与下游信号元件的相互作用。
7. 阻止ERBB3与其信号伙伴（特别是与其形成最强效促有丝分裂信号二聚体的ERBB2）的二聚化，可能为抑制整个Erbb网络致癌信号传导提供有效方法。

英文摘要：

Aberrant receptor expression or functioning of the epidermal growth factor receptor (Erbb) family plays a crucial part in the development and evolution of cancer. Inhibiting the signalling activity of individual receptors in this family has advanced the treatment of a range of human cancers. In this Review we re-evaluate the role of two important family members, ERBB2 (also known as HER2) and ERBB3 (also known as HER3), and explore the mechanisms of action and preclinical and clinical data for new therapies that target signalling through these pivotal receptors. These new therapies include tyrosine kinase inhibitors, antibody–chemotherapy conjugates, heat-shock protein inhibitors and antibodies that interfere with the formation of ERBB2–ERBB3 dimers.

摘要翻译： 

表皮生长因子受体（Erbb）家族的受体表达异常或功能异常，在癌症的发生和演变中起着关键作用。抑制该家族中单个受体的信号活性，已推进了多种人类癌症的治疗。在本综述中，我们重新评估了两个重要家族成员ERBB2（又称HER2）和ERBB3（又称HER3）的作用，并探讨了针对这些关键受体信号传导的新疗法的作用机制以及临床前和临床数据。这些新疗法包括酪氨酸激酶抑制剂、抗体-化疗偶联物、热休克蛋白抑制剂以及干扰ERBB2-ERBB3二聚体形成的抗体。

原文链接：

Novel anticancer targets: revisiting ERBB2 and discovering ERBB3