文章：

上皮恶性肿瘤中的酪氨酸激酶基因重排

Tyrosine kinase gene rearrangements in epithelial malignancies

原文发布日期：2013-10-17

DOI: 10.1038/nrc3612

类型: Review Article

开放获取: 否

要点：

1. Chromosomal rearrangements that lead to oncogenic kinase activation are an emerging paradigm in epithelial cancers.
2. Ten different tyrosine kinases have currently been identified as fusion kinases in various different epithelial tumours. Tyrosine kinase gene rearrangements generally define molecularly distinct subsets of patients.
3. Cancers that harbour tyrosine kinase gene rearrangements express activated fusion kinases that drive the initiation and progression of malignancy. These cancers become dependent on (or 'addicted' to) continued signalling from the oncogenic fusion kinase.
4. Several tyrosine kinase inhibitors have been shown to be active in cancers that harbour specific tyrosine kinase fusions, which validates these fusion kinases as bona fide targets. In the case of anaplastic lymphoma kinase (ALK)-rearranged lung cancers, ALK inhibitors like crizotinib have become a standard therapy.
5. Multiplexed genetic analyses that include screening for tyrosine kinase fusions will help to accelerate the process of target discovery and clinical validation.

要点翻译：

1. 导致致癌激酶活化的染色体重排是上皮癌中一种新兴的发病机制。
2. 目前已在多种上皮肿瘤中发现十种不同的酪氨酸激酶作为融合激酶存在。酪氨酸激酶基因重排通常从分子层面定义了独特的患者亚群。
3. 携带酪氨酸激酶基因重排的癌症会表达激活的融合激酶，这些激酶驱动恶性肿瘤的发生与发展。此类癌症会持续依赖（或称“成瘾”于）致癌融合激酶的信号传导。
4. 研究证实多种酪氨酸激酶抑制剂对携带特定酪氨酸激酶融合的癌症具有活性，这验证了这些融合激酶作为有效治疗靶点的地位。以间变性淋巴瘤激酶（ALK）重排型肺癌为例，ALK抑制剂（如克唑替尼）已成为标准治疗方案。
5. 包含酪氨酸激酶融合筛查的多重基因分析将有助于加速靶点发现和临床验证的进程。

英文摘要：

Chromosomal rearrangements that lead to oncogenic kinase activation are observed in many epithelial cancers. These cancers express activated fusion kinases that drive the initiation and progression of malignancy, and often have a considerable response to small-molecule kinase inhibitors, which validates these fusion kinases as 'druggable' targets. In this Review, we examine the aetiologic, pathogenic and clinical features that are associated with cancers harbouring oncogenic fusion kinases, including anaplastic lymphoma kinase (ALK), ROS1 and RET. We discuss the clinical outcomes with targeted therapies and explore strategies to discover additional kinases that are activated by chromosomal rearrangements in solid tumours.

摘要翻译： 

导致致癌激酶激活的染色体重排在许多上皮癌中可见。这些癌症表达活化的融合激酶，驱动恶性肿瘤的发生与进展，且往往对小分子激酶抑制剂有显著反应，从而验证了这些融合激酶作为“可成药”靶点的价值。本综述回顾了携带致癌融合激酶（包括间变性淋巴瘤激酶（ALK）、ROS1 和 RET）癌症的病原学、致病机制及临床特征，讨论了靶向治疗的临床结局，并探讨在实体瘤中发现由染色体重排激活的其他激酶的策略。

原文链接：

Tyrosine kinase gene rearrangements in epithelial malignancies