title: Response of experimental malignant melanoma models to the pan-Aurora kinase inhibitor VE-465.
abstract: Aurora kinases represent promising novel cancer therapy targets. Genomic analyses of human cutaneous melanoma (CMM) models (N = 51, low passage) by classical and/or array CGH revealed frequent gains at chromosome 20q (65%, amplifications in 45%) repeatedly including the Aurora A gene locus. Accordingly, the majority of CMM cell cultures overexpressed Aurora A when compared to proliferating non-malignant cells. Moreover, CMM cells even when arrested in G1/S cell cycle phase contained readily detectable levels of Aurora A indicating incomplete degradation during mitosis. Already at low concentrations (10-100 nm), long-term (7-10 days) application of the pan-Aurora kinase inhibitor VE-465 completely prevented colony formation in all CMM models tested. In contrast, blockade of cell survival/proliferation and DNA synthesis as well as the induction of apoptosis by VE-465 distinctly differed in short-term experiments (up to 72 h exposure). Both cell cycle arrest and DNA synthesis blockade depended on the level of VE-465-mediated p53/p21 activation while p53/p21 unresponsiveness led to repetitive endoreduplication (>8n DNA content). In contrast, apoptosis induction by VE-465 and Aurora A siRNA did not correlate with p53/p21 responsiveness and DNA synthesis blockade. Moreover, application of the Aurora B-specific inhibitor ZM447439 and siRNA was less efficient to induce CMM cell death proofing that apoptosis induction by VE-465 depended predominantly on Aurora A targeting. In combination experiments with chemotherapeutic agents, VE-465 acted additive to antagonistic when applied concomitantly but in several cases even synergistic when applied consecutively. In summary, we suggest that the Aurora A kinase might represent a promising target of well-designed novel antimelanoma strategies.
authors.affiliation: Institute of Cancer Research, Clinics for Medicine I, Medical University Vienna, Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.forename: Daniela
authors.initials: D
authors.lastname: Lötsch
authors.forename: Sabine
authors.initials: S
authors.lastname: Spiegl-Kreinecker
authors.forename: Florian
authors.initials: F
authors.lastname: Jantscher
authors.forename: Hewig
authors.initials: H
authors.lastname: Sutterlüty
authors.forename: Michael
authors.initials: M
authors.lastname: Micksche
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002877:Chromosomes, Human / Q000235:genetics; D004357:Drug Synergism; D005784:Gene Amplification / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064107:Aurora Kinase B; D064127:Aurora Kinases; D053179:Caspase 7; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576921:AURKB protein, human