title: Aurora kinases as targets in drug-resistant neuroblastoma cells.
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.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany; Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Michaelis
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Selt
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Rothweiler
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Löschmann
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Nüsse
authors.affiliation: Leibniz-Institute Deutsche Sammlung für Mikroorganismen und Zellkulturen GmbH, Braunschweig, Germany.
authors.forename: Wilhelm G
authors.initials: WG
authors.lastname: Dirks
authors.affiliation: Institut für Rechtsmedizin, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Zehner
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Frankfurt am Main, Germany.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D003521:Cyclopropanes; D011720:Pyrazoles
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D001381:Azepines; D006657:Histones; D007093:Imidazoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D051736:Proto-Oncogene Proteins c-mdm2; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; C513055:ABCB1 protein, human; C550258:MLN 8237; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; C482205:nutlin 3; C497206:MDM2 protein, human; C576917:AURKA protein, human; C576921:AURKB protein, human