Journal article
Aurora a is critical for survival in HPV-transformed cervical cancer
B Gabrielli, F Bokhari, MV Ranall, ZY Oo, AJ Stevenson, W Wang, M Murrell, M Shaikh, S Fallaha, D Clarke, M Kelly, K Sedelies, M Christensen, S McKee, G Leggatt, P Leo, D Skalamera, HP Soyer, TJ Gonda, NAJ McMillan
Molecular Cancer Therapeutics | AMER ASSOC CANCER RESEARCH | Published : 2015
Abstract
Human papillomavirus (HPV) is the causative agent in cervical cancer. HPV oncogenes are major drivers of the transformed phenotype, and the cancers remain addicted to these oncogenes. A screen of the human kinome has identified inhibition of Aurora kinase A (AURKA) as being synthetically lethal on the background of HPV E7 expression. The investigational AURKA inhibitor MLN8237/Alisertib selectively promoted apoptosis in the HPV cancers. The apoptosis was driven by an extended mitotic delay in the Alisertib-treated HPV E7-expressing cells. This had the effect of reducing Mcl-1 levels, which is destabilized in mitosis, and increasing BIM levels, normally destabilized by Aurora A in mitosis. Ov..
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Funding Acknowledgements
This work was supported by grants from the National Health and Medical Research Council (NHMRC) Australia (to B. Gabrielli and N.A.J. McMillan), Australian Cancer Research Fund (to T.J. Gonda), Cancer Council Queensland (to N.A.J. McMillan), Worldwide Cancer Research (formerly Association for International Cancer Research; to B. Gabrielli) and The University of Queensland Diamantina Institute. F. Bokhari was supported by a scholarship from The Medical Service Division, Ministry of Defense, Saudi Arabia. B. Gabrielli is an NHMRC Senior Research Fellow.