title: 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.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. brianG@uq.edu.au n.mcmillan@griffith.edu.au.
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Fawzi
authors.initials: F
authors.lastname: Bokhari
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Max V
authors.initials: MV
authors.lastname: Ranall
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Zay Yar
authors.initials: ZY
authors.lastname: Oo
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stevenson
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Weili
authors.initials: W
authors.lastname: Wang
authors.affiliation: Menzies Health Institute Queensland, School of Medical Science, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Murrell
authors.affiliation: Menzies Health Institute Queensland, School of Medical Science, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Mushfiq
authors.initials: M
authors.lastname: Shaikh
authors.affiliation: Menzies Health Institute Queensland, School of Medical Science, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Sora
authors.initials: S
authors.lastname: Fallaha
authors.affiliation: Menzies Health Institute Queensland, School of Medical Science, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Clarke
authors.affiliation: Menzies Health Institute Queensland, School of Medical Science, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Madison
authors.initials: M
authors.lastname: Kelly
authors.affiliation: Mater Research, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Karin
authors.initials: K
authors.lastname: Sedelies
authors.affiliation: Mater Research, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Melinda
authors.initials: M
authors.lastname: Christensen
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Sara
authors.initials: S
authors.lastname: McKee
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Graham
authors.initials: G
authors.lastname: Leggatt
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Leo
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Dubravka
authors.initials: D
authors.lastname: Skalamera
authors.affiliation: Dermatology Research Centre, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: H Peter
authors.initials: HP
authors.lastname: Soyer
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gonda
authors.affiliation: Menzies Health Institute Queensland, School of Medical Science, Griffith University, Gold Coast, Queensland, Australia. brianG@uq.edu.au n.mcmillan@griffith.edu.au.
authors.forename: Nigel A J
authors.initials: NA
authors.lastname: McMillan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001381:Azepines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis / Q000235:genetics; D027383:Papillomaviridae / Q000235:genetics / Q000472:pathogenicity; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001381:Azepines; C579095:MCL1 protein, human; C550258:MLN 8237; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050725:Papillomavirus E7 Proteins; D011743:Pyrimidines; C576917:AURKA protein, human; D064096:Aurora Kinase A