Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742, USA.
Pharmacol Res. 2013 Feb;68(1):68-94. doi: 10.1016/j.phrs.2012.11.007. Epub 2012 Nov 28.
Anaplastic lymphoma kinase was first described in 1994 as the NPM-ALK fusion protein that is expressed in the majority of anaplastic large-cell lymphomas. ALK is a receptor protein-tyrosine kinase that was more fully characterized in 1997. Physiological ALK participates in embryonic nervous system development, but its expression decreases after birth. ALK is a member of the insulin receptor superfamily and is most closely related to leukocyte tyrosine kinase (Ltk), which is a receptor protein-tyrosine kinase. Twenty different ALK-fusion proteins have been described that result from various chromosomal rearrangements, and they have been implicated in the pathogenesis of several diseases including anaplastic large-cell lymphoma, diffuse large B-cell lymphoma, and inflammatory myofibroblastic tumors. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The formation of dimers by the amino-terminal portion of the ALK fusion proteins results in the activation of the ALK protein kinase domain that plays a key role in the tumorigenic process. Downstream signaling from ALK fusion proteins involves the Ras/Raf/MEK/ERK1/2 cell proliferation module and the JAK/STAT cell survival pathway. Furthermore, nearly two dozen ALK activating mutations participate in the pathogenesis of childhood neuroblastomas along with ALK overexpression. The occurrence of oncogenic ALK, particularly in non-small cell lung cancer, has generated considerable interest and effort in developing ALK inhibitors. Currently, crizotinib has been approved by the US Food and Drug Administration for the treatment of ALK-positive non-small cell lung cancer along with an approved fluorescence in situ hybridization kit used for the diagnosis of the disease. The emergence of crizotinib drug resistance with a median occurrence at approximately 10 months after the initiation of therapy has stimulated the development of second-generation drugs for the treatment of non-small cell lung cancer and other disorders. About 28% of the cases of crizotinib resistance are related to nearly a dozen different mutations of ALK in the EML4-ALK fusion protein; the other cases of resistance are related to the upregulation of alternative signaling pathways or to undefined mechanisms. It is remarkable that the EML4-ALK fusion protein was discovered in 2007 and crizotinib was approved for the treatment of ALK-positive non-small cell lung cancer in 2011, which is a remarkably short timeframe in the overall scheme of drug discovery.
间变性淋巴瘤激酶于 1994 年首次被描述为 NPM-ALK 融合蛋白，该蛋白在大多数间变大细胞淋巴瘤中表达。ALK 是一种受体蛋白酪氨酸激酶，于 1997 年得到更全面的描述。生理上的 ALK 参与胚胎神经系统的发育，但出生后其表达减少。ALK 是胰岛素受体超家族的成员，与白细胞酪氨酸激酶（Ltk）最为密切相关，Ltk 是一种受体蛋白酪氨酸激酶。已经描述了 20 种不同的 ALK 融合蛋白，它们是由各种染色体重排引起的，与包括间变大细胞淋巴瘤、弥漫性大 B 细胞淋巴瘤和炎症性肌纤维母细胞瘤在内的几种疾病的发病机制有关。EML4-ALK 融合蛋白和其他四种 ALK 融合蛋白在约 5%的非小细胞肺癌的发展中起着重要作用。ALK 融合蛋白的氨基端部分形成二聚体，导致 ALK 蛋白激酶结构域的激活，该结构域在肿瘤发生过程中起着关键作用。ALK 融合蛋白的下游信号涉及 Ras/Raf/MEK/ERK1/2 细胞增殖模块和 JAK/STAT 细胞存活途径。此外，近二十几种 ALK 激活突变与 ALK 过表达一起参与儿童神经母细胞瘤的发病机制。致癌性 ALK 的发生，特别是在非小细胞肺癌中，引起了人们极大的兴趣，并努力开发 ALK 抑制剂。目前，克唑替尼已被美国食品和药物管理局批准用于治疗 ALK 阳性非小细胞肺癌，同时也批准了一种用于诊断该疾病的荧光原位杂交试剂盒。在开始治疗后约 10 个月，克唑替尼耐药的出现刺激了第二代药物的开发，用于治疗非小细胞肺癌和其他疾病。约 28%的克唑替尼耐药与 EML4-ALK 融合蛋白中近十几种不同的 ALK 突变有关；其他耐药与替代信号通路的上调或未定义的机制有关。值得注意的是，EML4-ALK 融合蛋白于 2007 年被发现，克唑替尼于 2011 年被批准用于治疗 ALK 阳性非小细胞肺癌，这在药物发现的整体框架中是一个非常短的时间框架。
