2. Academic Validation
  3. Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis

Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis

  • Sci Rep. 2016 Jan 20;6:19423. doi: 10.1038/srep19423.
Yongfeng Wang 1 2,  Long Wang 3 4,  Shan Guan 2,  Wenming Cao 3 5,  Hao Wang 3 6,  Zhenghu Chen 2,  Yanling Zhao 2,  Yang Yu 2,  Huiyuan Zhang 2,  Jonathan C Pang 2,  Sophia L Huang 2,  Yo Akiyama 2,  Yifan Yang 2,  Wenjing Sun 7,  Xin Xu 2,  Yan Shi 7,  Hong Zhang 3,  Eugene S Kim 7,  Jodi A Muscal 2,  Fengmin Lu 1,  Jianhua Yang 2
Affiliations

Affiliations

  • 1 Department of Microbiology, Peking University Health Science Center, Beijing 100191, China.
  • 2 Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 3 Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
  • 4 Department of Acupuncture, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, China.
  • 5 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
  • 6 Department of Hepatopancreatobiliary Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
  • 7 Division of Pediatric Surgery, Michael E. DeBakey Department of Pediatric Surgery, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
PMID: 26786851 DOI: 10.1038/srep19423
Abstract

ALK receptor tyrosine kinase has been shown to be a therapeutic target in neuroblastoma. Germline ALK activating mutations are responsible for the majority of hereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in sporadic cases of advanced NB. Crizotinib, a first-line therapy in the treatment of advanced non-small cell lung Cancer (NSCLC) harboring ALK rearrangements, demonstrates striking efficacy against ALK-rearranged NB. However, crizotinib fails to effectively inhibit the activity of ALK when activating mutations are present within its kinase domain, as with the F1174L mutation. Here we show that a new ALK inhibitor AZD3463 effectively suppressed the proliferation of NB cell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and D1091N) by blocking the ALK-mediated PI3K/Akt/mTOR pathway and ultimately induced Apoptosis and Autophagy. In addition, AZD3463 enhanced the cytotoxic effects of doxorubicin on NB cells. AZD3463 also exhibited significant therapeutic efficacy on the growth of the NB tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models. These results indicate that AZD3463 is a promising therapeutic agent in the treatment of NB.

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