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

Jiaxiong Lu, Shan Guan, Yanling Zhao, Yang Yu, Sarah E. Woodfield, Huiyuan Zhang, Kristine L. Yang, Shayahati Bieerkehazhi, Lin Qi, Xiaonan Li, Jerry Gu, Xin Xu, Jingling Jin, Jodi A. Muscal, Tianshu Yang, Guo Tong Xu, Jianhua Yang*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)61-68
Number of pages8
JournalCancer Letters
Volume400
DOIs
StatePublished - Aug 1 2017

Keywords

  • ALK inhibitor
  • Alectinib
  • Apoptosis
  • Neuroblastoma
  • PI3K/Akt/mTOR

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Lu, J., Guan, S., Zhao, Y., Yu, Y., Woodfield, S. E., Zhang, H., Yang, K. L., Bieerkehazhi, S., Qi, L., Li, X., Gu, J., Xu, X., Jin, J., Muscal, J. A., Yang, T., Xu, G. T., & Yang, J. (2017). 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 Letters, 400, 61-68. https://doi.org/10.1016/j.canlet.2017.04.022