Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma.
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.
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.|Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
Roberto Jose
RJ
Diaz
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Brian
B
Golbourn
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Claudia
C
Faria
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Daniel
D
Picard
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
David
D
Shih
Analytical Facility for Bioactive Molecules, The Hospital for Sick Children, Toronto, Ontario, Canada.
Denis
D
Raynaud
Analytical Facility for Bioactive Molecules, The Hospital for Sick Children, Toronto, Ontario, Canada.
Michael
M
Leadly
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Danielle
D
MacKenzie
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Melissa
M
Bryant
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Matthew
M
Bebenek
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Christian A
CA
Smith
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.|Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
Michael D
MD
Taylor
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.
Annie
A
Huang
The Hospital for Sick Children. Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada.|Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.|Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
James T
JT
Rutka
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C489427:MYC protein, human; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011799:Quinazolines; C531556:AZD 1152-HQPA; C576921:AURKB protein, human; D064107:Aurora Kinase B