PLoS ONE (Jan 2014)

Aurora kinases as targets in drug-resistant neuroblastoma cells.

  • Martin Michaelis,
  • Florian Selt,
  • Florian Rothweiler,
  • Nadine Löschmann,
  • Benedikt Nüsse,
  • Wilhelm G Dirks,
  • Richard Zehner,
  • Jindrich Cinatl

DOI
https://doi.org/10.1371/journal.pone.0108758
Journal volume & issue
Vol. 9, no. 9
p. e108758

Abstract

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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.