STM：ALK抑制剂TAE-684能使ALK突变型神经母细胞瘤完全消退

最近发现在10％的散发神经母细胞瘤和大多数家族性神经母细胞瘤患者中，存在激活的间变性淋巴瘤激酶（ALK）基因突变，。然而，在肿瘤发生中ALK突变的作用仍然是难以捉摸的。

7月4日，Sci Transl Med杂志报道，有针对性的表达最常见和最具侵袭性的突变类型ALK-F1174L可诱发小鼠的神经母细胞瘤。这些诱发的小鼠肿瘤在形态，转移模式，基因表达等方面均与人类神经母细胞瘤相似。并且，小鼠肿瘤同样存在神经分泌囊泡以及突触结构。

这个ALK驱动的神经母细胞瘤小鼠模型的精确模拟再现了该疾病的基因谱。神经母细胞瘤小鼠模型的染色体畸变类似于那些在人类神经母细胞瘤发生的畸变，包括17Q增益和MYCN基因扩增。针对性的ALK-F1174L和MYCN基因共表达显示了强大的协同作用，能以最小的染色体畸变诱导出神经母细胞瘤。这提示如果两种癌基因蛋白同时发生突变，则肿瘤的诱发仅需要较少的二次基因突变打击即可发生。

应用ALK抑制剂TAE-684治疗ALK-F1174L转基因小鼠，可诱导的肿瘤完全消退。这表明肿瘤细胞依赖于ALK-F1174L活性。研究者认为：在ALK的激酶结构域的激活突变足以诱导神经母细胞瘤的发生，ALK抑制剂对于治疗ALK突变的人类神经母细胞瘤具有很好的应用前景。

doi:10.1016/j.cell.2011.10.017
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Targeted Expression of Mutated ALK Induces Neuroblastoma in Transgenic Mice

Lukas C. Heukamp1,*,Theresa Thor2,*,Alexander Schramm2,Katleen De Preter3,Candy Kumps3,Bram De Wilde3,Andrea Odersky2,Martin Peifer4,5,Sven Lindner2,Annika Spruessel2,Filip Pattyn3,Pieter Mestdagh3,Bj?rn Menten3,Steffi Kuhfittig-Kulle2,Annette Künkele2,Katharina K?nig1,Lydia Meder1,Sampurna Chatterjee4,Roland T. Ullrich4,Stefanie Schulte2,Jo Vandesompele3,Frank Speleman3,Reinhard Büttner1,Angelika Eggert2 andJohannes H. Schulte2,?

 Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role of mutated ALK in tumorigenesis remains elusive. We demonstrate that targeted expression of the most frequent and aggressive variant, ALKF1174L, is tumorigenic in mice. Tumors resembled human neuroblastomas in morphology, metastasis pattern, gene expression, and the presence of neurosecretory vesicles as well as synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated the genetic spectrum of the disease. Chromosomal aberrations were syntenic to those in human neuroblastoma, including 17q gain and MYCN oncogene amplification. Targeted ALKF1174L and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted. Treatment of ALKF1174L transgenic mice with the ALK inhibitor TAE-684 induced complete tumor regression, indicating that tumor cells were addicted to ALKF1174L activity. We conclude that an activating mutation within the ALK kinase domain is sufficient to induce neuroblastoma development, and ALK inhibitors show promise for treating human neuroblastomas harboring ALK mutations.