Bruton's tyrosine kinase potentiates ALK signaling and serves as a potential therapeutic target of neuroblastoma
Bruton's tyrosine kinase potentiates ALK signaling and serves as a potential therapeutic target of neuroblastoma
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Bruton 酪氨酸激酶增强 ALK 信号传导，可作为神经母细胞瘤的潜在治疗靶点
DOI：
10.1038/s41388-018-0397-7
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发表时间：
2018-11-22
期刊：
影响因子：
8
通讯作者：
Zhao, Hui
中科院分区：
文献类型：
--
作者：
Li, Tianfeng;Deng, Yi;Zhao, Hui
间变性淋巴瘤激酶（ALK）的异常激活可引起散发性和家族性神经母细胞瘤。使用蛋白质组学方法，我们确定了布鲁顿的酪氨酸激酶（BTK）作为一种新的ALK相互作用伴侣，并通过免疫共沉淀证实了物理相互作用。BTK在神经母细胞瘤细胞系和肿瘤组织中表达。其高表达与神经母细胞瘤患者的低无复发生存概率相关。从机制上讲，我们证明了BTK在神经母细胞瘤中增强ALK介导的信号传导，并通过减少ALK泛素化来增加ALK稳定性。ALKWT和ALKF1174L都可以诱导BTK磷酸化，并且观察到ALKF1174L的更高能力。此外，BTK抑制剂伊曲替尼可有效抑制裸鼠神经母细胞瘤异种移植瘤的生长，伊曲替尼与ALK抑制剂克唑替尼联用可进一步增强抑制作用。我们的研究为使用伊鲁替尼或伊鲁替尼与ALK抑制剂联合治疗ALK阳性神经母细胞瘤的临床试验提供了强有力的依据。
Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton's tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma cell lines and tumor tissues. Its high expression correlates with poor relapse-free survival probability of neuroblastoma patients. Mechanistically, we demonstrated that BTK potentiates ALK-mediated signaling in neuroblastoma, and increases ALK stability by reducing ALK ubiquitination. Both ALKWT and ALKF1174L can induce BTK phosphorylation and higher capacity of ALKF1174L is observed. Furthermore, the BTK inhibitor ibrutinib can effectively inhibit the growth of neuroblastoma xenograft in nude mice, and the combination of ibrutinib and the ALK inhibitor crizotinib further enhances the inhibition. Our study provides strong rationale for clinical trial of ALK-positive neuroblastoma using ibrutinib or the combination of ibrutinib and ALK inhibitors.