2. Academic Validation
  3. The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model

  • Cancer Lett. 2017 Aug 1;400:61-68. doi: 10.1016/j.canlet.2017.04.022.
Jiaxiong Lu 1,  Shan Guan 2,  Yanling Zhao 2,  Yang Yu 3,  Sarah E Woodfield 3,  Huiyuan Zhang 2,  Kristine L Yang 2,  Shayahati Bieerkehazhi 2,  Lin Qi 4,  Xiaonan Li 4,  Jerry Gu 2,  Xin Xu 2,  Jingling Jin 2,  Jodi A Muscal 5,  Tianshu Yang 6,  Guo-Tong Xu 7,  Jianhua Yang 8
Affiliations

Affiliations

  • 1 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.
  • 2 Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 3 Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 4 Pediatrics-Oncology, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
  • 5 Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address: jmuscal@bcm.edu.
  • 6 Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200092, China. Electronic address: tianshuy@tongji.edu.cn.
  • 7 Department of Ophthalmology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200092, China. Electronic address: gtxu@tongji.edu.cn.
  • 8 Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address: jianhuay@bcm.edu.
PMID: 28455243 DOI: 10.1016/j.canlet.2017.04.022
Abstract

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.

Keywords

ALK inhibitor; Alectinib; Apoptosis; Neuroblastoma; PI3K/Akt/mTOR.

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