Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma
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Roberto Jose Diaz1,2,3,*, Brian Golbourn1,*, Claudia Faria1, Daniel Picard1, David Shih1, Denis Raynaud4, Michael Leadly4, Danielle MacKenzie1, Melissa Bryant1, Matthew Bebenek1, Christian A. Smith1, Michael D. Taylor1,2,3, Annie Huang1 and James T. Rutka1,2,3
1 The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada
2 Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada
3 Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
4 Analytical Facility for Bioactive Molecules, The Hospital for Sick Children, Toronto, Ontario, Canada
* These authors contributed equally to this work
James T. Rutka, email:
Keywords: Aurora kinase, medulloblastoma, tumor biology, molecular therapy,cell-cycle
Received: June 29, 2014 Accepted: December 24, 2014 Published: December 31, 2014
Medulloblastoma comprises four molecular subgroups of which Group 3 medulloblastoma is characterized by MYC amplification and MYC overexpression. Lymphoma cells expressing high levels of MYC are susceptible to apoptosis following treatment with inhibitors of mitosis. One of the key regulatory kinases involved in multiple stages of mitosis is Aurora kinase B. We hypothesized that medulloblastoma cells that overexpress MYC would be uniquely sensitized to the apoptotic effects of Aurora B inhibition. The specific inhibition of Aurora kinase B was achieved in MYC- overexpressing medulloblastoma cells with AZD1152-HQPA. MYC overexpression sensitized medulloblastoma cells to cell death upon Aurora B inhibition. This process was found to be independent of endoreplication. Using both flank and intracranial cerebellar xenografts we demonstrate that tumors formed from MYC-overexpressing medulloblastoma cells show a response to Aurora B inhibition including growth impairment and apoptosis induction. Lastly, we show the distribution of AZD1152-HQPA within the mouse brain and the ability to inhibit intracranial tumor growth and prolong survival in mice bearing tumors formed from MYC-overexpressing medulloblastoma cells. Our results suggest the potential for therapeutic application of Aurora kinase B inhibitors in the treatment of Group 3 medulloblastoma.
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