Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer.

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.

• 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 12 Pg. 2753-61 (Dec 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 26516156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Azepines
• MCL1 protein, human
• MLN 8237
• Myeloid Cell Leukemia Sequence 1 Protein
• Papillomavirus E7 Proteins
• Pyrimidines
• AURKA protein, human
• Aurora Kinase A

Topics

• Animals
• Apoptosis (drug effects)
• Aurora Kinase A (antagonists & inhibitors, biosynthesis)
• Azepines (administration & dosage)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Female
• Humans
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein (biosynthesis, genetics)
• Papillomaviridae (genetics, pathogenicity)
• Papillomavirus E7 Proteins (metabolism)
• Pyrimidines (administration & dosage)
• Uterine Cervical Neoplasms (drug therapy, genetics, virology)
• Xenograft Model Antitumor Assays