Lu Jiaxiong, Guan Shan, Zhao Yanling, Yu Yang, Woodfield Sarah E, Zhang Huiyuan, Yang Kristine L, Bieerkehazhi Shayahati, Qi Lin, Li Xiaonan, Gu Jerry, Xu Xin, Jin Jingling, Muscal Jodi A, Yang Tianshu, Xu Guo-Tong, Yang Jianhua
Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200092, China; Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
Cancer Lett. 2017 Aug 1;400:61-68. doi: 10.1016/j.canlet.2017.04.022. Epub 2017 Apr 26.
Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.
间变性淋巴瘤激酶（ALK）的激活种系突变在大多数遗传性神经母细胞瘤（NB）病例中出现，并且ALK的组成型活性激酶活性促进NB中的细胞增殖和存活。因此，ALK激酶是NB的潜在治疗靶点。在本研究中，我们表明新型ALK抑制剂阿来替尼通过阻断ALK介导的PI3K/Akt/mTOR信号传导，有效抑制了具有野生型ALK或突变型ALK（F1174L和D1091N）的NB细胞系中的细胞增殖并诱导凋亡。此外，阿来替尼增强了阿霉素诱导的NB细胞的细胞毒性和凋亡。此外，阿来替尼在原位异种移植NB小鼠模型中诱导凋亡。同样，在TH-MYCN转基因小鼠模型中，阿来替尼导致肿瘤生长减少并延长存活时间。这些结果表明阿来替尼可能是治疗NB的有前景的治疗药物。
