文章：

ALK受体酪氨酸激酶在人类癌症生物学中的机制研究

Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

原文发布日期：2013-08-23

DOI: 10.1038/nrc3580

类型: Review Article

开放获取: 否

要点：

1. Anaplastic lymphoma kinase (ALK) is involved in the initiation and progression of many different cancer types, including lymphomas, neuroblastoma and non-small-cell lung cancer. It is clear that ALK can be activated by translocation, as well as by mutation. The ALK locus is a hotspot for activating translocation events, with 22 different translocation partners identified. The resulting ALK fusion proteins are found in a wide range of cancer types. An alternative mechanism for ALK activation is through point mutation of the ALK locus, most commonly within the kinase domain, as reported in patients with neuroblastoma and thyroid cancer.
2. The physiological function of ALK in mammals is enigmatic, although it is clear that ALK is not required for viability, as Alk^−/− mice are viable. The role of ALK in model systems, such as Drosophila melanogaster, Caenorhabditis elegans and Danio rerio, is more clearly defined in development, with ALK signalling used repeatedly in a spatially and temporally regulated manner. In both D. melanogaster and C. elegans, ALK also has genetically defined ligands.
3. The spatial and temporal expression pattern of the different oncogenic ALK fusion proteins is determined by the fusion partners. Furthermore, although not well studied, comparisons of the different ALK fusion proteins suggest that they display differences in signalling and in transforming and tumorigenic potential.
4. The first clinically approved drug to target ALK — crizotinib — is a tyrosine kinase inhibitor (TKI) that was approved by the US Food and Drug Administration (FDA) for use in ALK-positive non-small-cell lung cancer. Recent reports suggest that ALK TKIs will be useful in the treatment of other less frequently occurring ALK-positive cancer types. A number of second-generation ALK TKIs are currently in clinical trials and are able to inhibit secondary 'resistance' mutations that are found in patients treated with crizotinib.
5. Several important issues remain to be addressed, such as cooperativity between ALK and other oncogenes and tumour suppressors, the differences in signalling output between different ALK oncogenes, the streamlined identification of ALK-positive patients in multiple cancer types, putative combinatorial drug strategies for patients and an explanation for why the ALK locus is a hotspot for translocation.

要点翻译：

1. 间变性淋巴瘤激酶（ALK）参与多种癌症的发生发展，包括淋巴瘤、神经母细胞瘤和非小细胞肺癌。目前明确ALK可通过基因易位和突变两种方式激活。ALK基因位点是激活型易位事件的高发区域，已发现22种不同的易位伙伴基因。由此产生的ALK融合蛋白广泛存在于各类癌症中。另一种ALK激活机制是通过基因位点突变实现，最常见的是激酶结构域内的点突变，这在神经母细胞瘤和甲状腺癌患者中已有报道。
2. 尽管ALK在哺乳动物中的生理功能尚不明确，但可以确定其并非维持生命所必需，因为Alk基因敲除小鼠能够正常存活。在果蝇、线虫和斑马鱼等模式生物中，ALK在发育过程中的作用更为明确，其信号传导以时空调控的方式反复参与发育过程。在果蝇和线虫中，ALK还存在遗传学上明确的配体。
3. 不同致癌性ALK融合蛋白的时空表达模式取决于其融合伙伴基因。此外，尽管研究尚不充分，但对比不同ALK融合蛋白显示，它们在信号传导、转化能力和致瘤潜力方面存在差异。
4. 首个获批用于靶向ALK的临床药物——克唑替尼，是一种酪氨酸激酶抑制剂（TKI），已获美国食品药品监督管理局（FDA）批准用于治疗ALK阳性非小细胞肺癌。近期研究表明ALK-TKI类药物也有望用于治疗其他较少见的ALK阳性癌症。多个第二代ALK-TKI目前正处于临床试验阶段，这些药物能够抑制克唑替尼治疗患者中出现的继发性耐药突变。
5. 仍有若干重要问题亟待解决：ALK与其他癌基因和抑癌基因的协同作用、不同ALK致癌基因信号输出的差异、多种癌症类型中ALK阳性患者的精准筛查、针对患者的潜在联合用药策略，以及ALK基因位点易位高发机制的解释等。

英文摘要：

The burgeoning field of anaplastic lymphoma kinase (ALK) in cancer encompasses many cancer types, from very rare cancers to the more prevalent non-small-cell lung cancer (NSCLC). The common activation of ALK has led to the use of the ALK tyrosine kinase inhibitor (TKI) crizotinib in a range of patient populations and to the rapid development of second-generation drugs targeting ALK. In this Review, we discuss our current understanding of ALK function in human cancer and the implications for tumour treatment.

摘要翻译： 

间变性淋巴瘤激酶（ALK）这一新兴研究领域涉及多种癌症类型，从极罕见癌症到更为常见的非小细胞肺癌（NSCLC）。ALK的普遍激活促使ALK酪氨酸激酶抑制剂（TKI）克唑替尼应用于各类患者群体，并推动了第二代ALK靶向药物的快速发展。在本综述中，我们探讨了目前对ALK在人类癌症中功能的理解及其对肿瘤治疗的影响。

原文链接：

Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology