A mouse model for EML4-ALK-positive lung cancer
A mouse model for EML4-ALK-positive lung cancer
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DOI：
10.1073/pnas.0805381105
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发表时间：
2008-12-16
影响因子：
11.1
通讯作者：
Mano, Hiroyuki
中科院分区：
文献类型：
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作者：
Soda, Manabu;Takada, Shuji;Mano, Hiroyuki
EML4-ALK是一种融合型蛋白酪氨酸激酶，在人类非小细胞肺癌（NSCLC）中由于反复染色体倒置而产生，inv (2)（p21p23）。虽然表达人EML4-ALK的小鼠3T3成纤维细胞在培养物中形成转化灶，在裸鼠中形成sc肿瘤，但这种融合蛋白是否在NSCLC的癌变中起重要作用尚不清楚。为了解决这个问题，我们现在已经建立了在肺泡上皮细胞中特异性表达EML4-ALK的转基因小鼠系。所有接受检测的转基因小鼠在出生后几周内，双肺都出现了数百个腺癌结节，证实了融合激酶的强致癌活性。尽管这些肿瘤在对照动物中呈进行性扩大，但口服一种ALK激酶活性的小分子抑制剂可使其迅速消失。同样，静脉注射表达EML4-ALK的3T3细胞在受体裸鼠中诱导致死性呼吸衰竭，而给予ALK抑制剂有效地清除了肿瘤负荷，提高了这些动物的存活率。这些数据共同强化了EML4-ALK在人类NSCLC发病机制中的关键作用，并为使用ALK抑制剂治疗这种难治性癌症提供了实验支持。
EML4-ALK is a fusion-type protein tyrosine kinase that is generated in human non-small-cell lung cancer (NSCLC) as a result of a recurrent chromosome inversion, inv (2)(p21p23). Although mouse 3T3 fibroblasts expressing human EML4-ALK form transformed foci in culture and s.c. tumors in nude mice, it has remained unclear whether this fusion protein plays an essential role in the carcinogenesis of NSCLC. To address this issue, we have now established transgenic mouse lines that express EML4-ALK specifically in lung alveolar epithelial cells. All of the transgenic mice examined developed hundreds of adenocarcinoma nodules in both lungs within a few weeks after birth, confirming the potent oncogenic activity of the fusion kinase. Although such tumors underwent progressive enlargement in control animals, oral administration of a small-molecule inhibitor of the kinase activity of ALK resulted in their rapid disappearance. Similarly, whereas i.v. injection of 3T3 cells expressing EML4-ALK induced lethal respiratory failure in recipient nude mice, administration of the ALK inhibitor effectively cleared the tumor burden and improved the survival of such animals. These data together reinforce the pivotal role of EML4-ALK in the pathogenesis of NSCLC in humans, and they provide experimental support for the treatment of this intractable cancer with ALK inhibitors.