TY - JOUR T1 - Aurora Kinases as Targets in Drug-Resistant Neuroblastoma Cells A1 - Michaelis, Martin A1 - Selt, Florian A1 - Rothweiler, Florian A1 - Löschmann, Nadine A1 - Nüsse, Benedikt A1 - Dirks, Wilhelm G. A1 - Zehner, Richard A1 - Cinatl, Jindrich, Jr Y1 - 2014/09/30 N2 - 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. JF - PLOS ONE JA - PLOS ONE VL - 9 IS - 9 UR - https://doi.org/10.1371/journal.pone.0108758 SP - e108758 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pone.0108758 ER -