Emerging importance of ALK in neuroblastoma.
Emerging importance of ALK in neuroblastoma.
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DOI：
10.1016/j.semcancer.2011.09.005
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发表时间：
2011-10
影响因子：
14.5
通讯作者：
George RE
中科院分区：
文献类型：
--
作者：
Azarova AM;Gautam G;George RE
自从最初描述间变性淋巴瘤激酶（ALK）的功能获得性突变以来，对该受体酪氨酸激酶在神经母细胞瘤发展中的作用以及作为潜在治疗靶点的兴趣已经升级。作为一个组，在所有神经母细胞瘤肿瘤的约8%中发现的全长ALK中的激活点突变在不同的临床阶段中均匀分布。然而，最常见的体细胞突变F1174L与MYCN癌基因的扩增有关。这种特征的组合似乎赋予比单独MYCN扩增更差的预后，表明这两种蛋白质对神经母细胞瘤形成的协同作用。事实上，F1174L在体内显示出比第二常见的激活突变R1275Q更强的转化活性，并且是对克唑替尼（一种即将上市的临床相关ALK抑制剂）的先天性和获得性耐药性的原因。这些进展使ALK成为神经母细胞瘤中真正的癌蛋白，并强调需要了解这种肿瘤中ALK介导的信号传导。本文综述了目前围绕ALK在正常发育和神经母细胞瘤发病机制中的作用的许多问题，并讨论了基于ALK抑制的临床有效靶向治疗的前景。
Since the original descriptions of gain-of function mutations in anaplastic lymphoma kinase (ALK), interest in the role of this receptor tyrosine kinase in neuroblastoma development and as a potential therapeutic target has escalated. As a group, the activating point mutations in full-length ALK, found in approximately 8% of all neuroblastoma tumors, are distributed evenly across different clinical stages. However, the most frequent somatic mutation, F1174L, is associated with amplification of the MYCN oncogene. This combination of features appears to confer a worse prognosis than MYCN amplification alone, suggesting a cooperative effect on neuroblastoma formation by these two proteins. Indeed, F1174L has shown more potent transforming activity in vivo than the second most common activating mutation, R1275Q, and is responsible for innate and acquired resistance to crizotinib, a clinically relevant ALK inhibitor that will soon be commercially available. These advances cast ALK as a bona fide oncoprotein in neuroblastoma and emphasize the need to understand ALK-mediated signaling in this tumor. This review addresses many of the current issues surrounding the role of ALK in normal development and neuroblastoma pathogenesis, and discusses the prospects for clinically effective targeted treatments based on ALK inhibition.
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影响因子：
3.7
作者：
George RE;Attiyeh EF;Li S;Moreau LA;Neuberg D;Li C;Fox EA;Meyerson M;Diller L;Fortina P;Look AT;Maris JM
通讯作者：
Maris JM
影响因子：
4
作者：
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通讯作者：
Brunet-de Carvalho, N
影响因子：
8
作者：
Iwahara, T;Fujimoto, J;Yamamoto, T
通讯作者：
Yamamoto, T
影响因子：
5.7
作者：
Christensen, James G.;Zou, Helen Y.;Los, Gerrit
通讯作者：
Los, Gerrit
影响因子：
11.5
作者：
De Brouwer, Sara;De Preter, Katleen;Speleman, Frank
通讯作者：
Speleman, Frank