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. Epub 2017 Apr 26.

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.

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects*
  • Carbazoles / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Inhibitory Concentration 50
  • Mice, Nude
  • Mice, Transgenic
  • Mutation
  • N-Myc Proto-Oncogene Protein / genetics*
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / enzymology
  • Neuroblastoma / genetics
  • Neuroblastoma / pathology
  • Phenotype
  • Phosphatidylinositol 3-Kinase / metabolism
  • Piperidines / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Tumor Burden / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Carbazoles
  • N-Myc Proto-Oncogene Protein
  • Piperidines
  • Protein Kinase Inhibitors
  • Doxorubicin
  • MTOR protein, human
  • Phosphatidylinositol 3-Kinase
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • alectinib