Aurora kinases as targets in drug-resistant neuroblastoma cells

PLoS One. 2014 Sep 30;9(9):e108758. doi: 10.1371/journal.pone.0108758. eCollection 2014.

Abstract

Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Aurora Kinase A / antagonists & inhibitors*
  • Aurora Kinase A / genetics
  • Aurora Kinase A / metabolism
  • Aurora Kinase B / antagonists & inhibitors*
  • Aurora Kinase B / genetics
  • Aurora Kinase B / metabolism
  • Azepines / pharmacology*
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Imidazoles / pharmacology
  • Neuroblastoma / drug therapy
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Phosphorylation / drug effects
  • Piperazines / pharmacology*
  • Primary Cell Culture
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Pyrimidines / pharmacology*
  • Signal Transduction
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents
  • Azepines
  • Histones
  • Imidazoles
  • MLN 8237
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Tumor Suppressor Protein p53
  • nutlin 3
  • VX680
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • AURKA protein, human
  • AURKB protein, human
  • Aurora Kinase A
  • Aurora Kinase B

Grant support

MM and JC were supported by Frankfurter Stiftung für krebskranke Kinder (www.kinderkrebs-frankfurt.de) and Frankfurter Stiftung für krebskranke Kinder (www.kinderkrebsstiftung-frankfurt.de). MM was also supported by Kent Cancer Trust (www.kentcancertrust.org.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.