Title |
Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer
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Published in |
Molecular Cancer Therapeutics, December 2015
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DOI | 10.1158/1535-7163.mct-15-0506 |
Pubmed ID | |
Authors |
Brian Gabrielli, Fawzi Bokhari, Max V Ranall, Zay Yar Oo, Alexander J Stevenson, Weili Wang, Melanie Murrell, Mushfiq Shaikh, Sora Fallaha, Daniel Clarke, Madison Kelly, Karin Sedelies, Melinda Christensen, Sara McKee, Graham Leggatt, Paul Leo, Dubravka Skalamera, H Peter Soyer, Thomas J Gonda, Nigel A J McMillan |
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 destabilised in mitosis, and increasing BIM levels, normally destabilised by Aurora A in mitosis. Over-expression of Mcl-1 reduced sensitivity to the drug. The level of HPV E7 expression influenced the extent of Alisertib-induced mitotic delay and Mcl-1 reduction. Xenograft experiments with three cervical cancer cell lines showed Alisertib inhibited growth of HPV and non-HPV xenografts during treatment. Growth of non-HPV tumours was delayed, but in two separate HPV cancer cell lines, regression with no resumption of growth was detected, even at 50 days post-treatment. A transgenic model of premalignant disease driven solely by HPV E7 also demonstrated sensitivity to drug treatment. Here we show for the first time that targeting of the Aurora A kinase in mice using drugs such as Alisertib results in a curative sterilising therapy may be useful in treating HPV-driven cancers. |
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