文章：

间变性淋巴瘤激酶在肿瘤发病中的作用

The anaplastic lymphoma kinase in the pathogenesis of cancer

原文发布日期：2008-01-01

DOI: 10.1038/nrc2291

类型: Review Article

开放获取: 否

要点：

1. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase first identified in a chromosomal translocation associated with some anaplastic large cell lymphomas (ALCL), a subset of T-cell non-Hodgkin lymphomas.
2. The function of the full-length ALK receptor is still poorly characterized. Recent data suggest that ALK is involved in neuronal cell differentiation and regeneration, synapse formation and muscle cell migration.
3. Recently, the interest on ALK in oncology has increased considerably, following the discovery of ALK translocations in a fraction of non-small-cell lung cancers and in other solid tumours.
4. In cancers, all translocations involving ALK produce fusion proteins with constitutive tyrosine kinase activity that in most cases derives from spontaneous dimerization induced by the different fusion partners.
5. Constitutive ALK activity in cancers results in the activation of several downstream pathways that are shared with other tyrosine kinases. Many of these pathways have already been characterized.
6. Constitutive ALK signalling induces cell transformation in vitro and in vivo by controlling key cellular processes such as cell-cycle progression, survival, cell migration and cell shaping.
7. ALK represents an attractive target for innovative combination therapies based on selective small-molecule inhibitors of its tyrosine kinase activity or on its use as an oncoantigen for tumour vaccination.

要点翻译：

1. 间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶，最初在与某些间变性大细胞淋巴瘤（ALCL）（T细胞非霍奇金淋巴瘤的一个亚群）相关的染色体易位中发现。
2. 全长ALK受体的功能仍不甚明确。近期数据表明，ALK参与神经元细胞分化和再生、突触形成以及肌细胞迁移。
3. 近来，随着在部分非小细胞肺癌和其他实体瘤中发现ALK易位，该激酶在肿瘤学领域的关注度显著提升。
4. 在癌症中，所有涉及ALK的易位都会产生具有组成型酪氨酸激酶活性的融合蛋白，这种活性在大多数情况下源于不同融合伴侣诱导的自发二聚化。
5. 癌症中ALK的组成型激活会导致多条下游通路被激活，这些通路与其他酪氨酸激酶所共享。其中许多通路已被明确表征。
6. 组成型ALK信号通过调控细胞周期进程、存活、细胞迁移和细胞形态等关键细胞过程，在体外和体内诱导细胞转化。
7. ALK基于其酪氨酸激酶活性的选择性小分子抑制剂，或作为肿瘤疫苗的肿瘤抗原，为创新性联合治疗提供了极具吸引力的靶点。

英文摘要：

Tyrosine kinases are involved in the pathogenesis of most cancers. However, few tyrosine kinases have been shown to have a well-defined pathogenetic role in lymphomas. The anaplastic lymphoma kinase (ALK) is the oncogene of most anaplastic large cell lymphomas (ALCL), driving transformation through many molecular mechanisms. In this Review, we will analyse how translocations or deregulated expression of ALK contribute to oncogenesis and how recent genetic or pharmacological tools, aimed at neutralizing its activity, can represent the basis for the design of powerful combination therapies.

摘要翻译： 

酪氨酸激酶参与大多数癌症的发病机制。然而，在淋巴瘤中，只有少数酪氨酸激酶被证实具有明确的发病作用。间变性淋巴瘤激酶（ALK）是大多数间变性大细胞淋巴瘤（ALCL）的致癌基因，通过多种分子机制驱动细胞转化。在本综述中，我们将分析ALK的易位或表达失调如何促进肿瘤发生，以及近期针对其中和活性的遗传或药理学工具如何成为设计强效联合治疗策略的基础。

原文链接：

The anaplastic lymphoma kinase in the pathogenesis of cancer