Aurora A is critical for survival in HPV-transformed cervical cancer

Gabrielli, Brian, Bokhari, Fawzi, Ranall, Max V., Oo, Zay Yar, Stevenson, Alexander J., Wang, Weili, Murrell, Melanie, Shaikh, Mushfiq, Fallaha, Sora, Clarke, Daniel, Kelly, Madison, Sedelies, Karin, Christensen, Melinda, McKee, Sara, Leggatt, Graham, Leo, Paul, Skalamera, Dubravka, Soyer, H. Peter, Gonda, Thomas J. and McMillan, Nigel A. J. (2015) Aurora A is critical for survival in HPV-transformed cervical cancer. Molecular Cancer Therapeutics, 14 12: 2753-2761. doi:10.1158/1535-7163.MCT-15-0506

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Author Gabrielli, Brian
Bokhari, Fawzi
Ranall, Max V.
Oo, Zay Yar
Stevenson, Alexander J.
Wang, Weili
Murrell, Melanie
Shaikh, Mushfiq
Fallaha, Sora
Clarke, Daniel
Kelly, Madison
Sedelies, Karin
Christensen, Melinda
McKee, Sara
Leggatt, Graham
Leo, Paul
Skalamera, Dubravka
Soyer, H. Peter
Gonda, Thomas J.
McMillan, Nigel A. J.
Title Aurora A is critical for survival in HPV-transformed cervical cancer
Journal name Molecular Cancer Therapeutics   Check publisher's open access policy
ISSN 1535-7163
1538-8514
Publication date 2015-10-29
Sub-type Article (original research)
DOI 10.1158/1535-7163.MCT-15-0506
Open Access Status Not Open Access
Volume 14
Issue 12
Start page 2753
End page 2761
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
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. Overexpression 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 tumors was delayed, but in two separate HPV cancer cell lines, regression with no resumption of growth was detected, even at 50 days after 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 sterilizing therapy that may be useful in treating HPV-driven cancers.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
Official 2016 Collection
UQ Diamantina Institute Publications
 
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Created: Wed, 23 Dec 2015, 08:23:36 EST by Dr Graham Leggatt on behalf of UQ Diamantina Institute