Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer
Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer
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DOI：
10.1073/pnas.1321937111
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发表时间：
2014-03-18
影响因子：
11.1
通讯作者：
Nikiforov, Yuri E.
中科院分区：
文献类型：
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作者：
Kelly, Lindsey M.;Barila, Guillermo;Nikiforov, Yuri E.
甲状腺癌是一种常见的内分泌恶性肿瘤，包括分化良好的癌症类型。后一种肿瘤的死亡率很高，缺乏有效的疗法。使用配对端RNA测序方法，我们报告了甲状腺癌中涉及变性淋巴瘤激酶（ALK）基因的重排的发现。其中最常见的一种涉及碱和纹状体（Strn）基因之间的融合，这是涉及染色体2的短臂的复杂重排的结果。STRN-ALK导致通过由盘旋的二聚体介导的二聚化的烷基激酶的组成型激活。 -STRN和激酶依赖性的甲状腺刺激性激素非依赖性甲状腺细胞增殖的结构域。此外，Strn-Alk的表达会在体外转化细胞，并在裸鼠中诱导肿瘤形成。 ALK抑制剂克里佐替尼和TAE684可以阻断Strn-Alk和ALK诱导的细胞生长的激酶活性。除了分化良好的乳头状癌外，发现Strn-Alk在分化较差和塑性甲状腺癌中的患病率更高，并且它与这些肿瘤中其他已知的驱动器突变没有重叠。我们的数据表明，Strn-Alk融合发生在具有高度侵略性甲状腺癌类型的患者中，并提供了初步证据，表明它可能代表这些患者的治疗靶点。
Thyroid cancer is a common endocrine malignancy that encompasses well-differentiated as well as dedifferentiated cancer types. The latter tumors have high mortality and lack effective therapies. Using a paired-end RNA-sequencing approach, we report the discovery of rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. The most common of these involves a fusion between ALK and the striatin (STRN) gene, which is the result of a complex rearrangement involving the short arm of chromosome 2. STRN-ALK leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN and to a kinase-dependent, thyroid-stimulating hormone-independent proliferation of thyroid cells. Moreover, expression of STRN-ALK transforms cells in vitro and induces tumor formation in nude mice. The kinase activity of STRN-ALK and the ALK-induced cell growth can be blocked by the ALK inhibitors crizotinib and TAE684. In addition to well-differentiated papillary cancer, STRN-ALK was found with a higher prevalence in poorly differentiated and anaplastic thyroid cancers, and it did not overlap with other known driver mutations in these tumors. Our data demonstrate that STRN-ALK fusion occurs in a subset of patients with highly aggressive types of thyroid cancer and provide initial evidence suggesting that it may represent a therapeutic target for these patients.