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Oral Oncol. 2018 Nov;86:105-112. doi: 10.1016/j.oraloncology.2018.09.006. Epub 2018 Sep 19.

Aurora kinases are a novel therapeutic target for HPV-positive head and neck cancers.

Author information

1
Menzies Health Institute Queensland, School of Dentistry and Oral Health, Griffith University, Southport, Queensland, Australia; Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia.
2
Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia; Department of Clinical Laboratory, Kaifeng Central Hospital, Kaifeng City, China.
3
Menzies Health Institute Queensland, School of Dentistry and Oral Health, Griffith University, Southport, Queensland, Australia; Dental Institute, King's College London, London, United Kingdom.
4
Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia.
5
Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia; Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
6
Department of Oral and Craniofacial Molecular Biology, VCU Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry, Richmond, VA, USA.
7
Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
8
Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia. Electronic address: n.mcmillan@griffith.edu.au.

Abstract

OBJECTIVES:

Human papilloma virus (HPV) is the main culprit in cancers of the cervix, penis, anus, skin, eye and head and neck. Current treatments for HPV cancers have not altered survival outcomes for 30 years and there is a significant lack of targeted therapeutic agents in the management of advanced HPV-related HNSCC. Here we show that survival and maintenance of HPV-positive HNC cells relies on the continuous expression of the major HPV oncogene, E7, and that Aurora kinases are critical for survival of high-risk HPV-positive HNC cells.

MATERIALS AND METHODS:

To assess the role of HPV E7 on HNC cell survival, RNA interference (RNAi) of the E7 gene was initially performed. Using an Aurora kinase inhibitor, Alisertib, the role of Aurora kinases in the carcinogenesis of HPV E7 positive HNC tumour lines was then investigated. An in vivo HNC xenograft model was also utilised to assess loss of tumour volume in response to RNAi E7 gene silencing and Alisertib treatment.

RESULTS:

RNAi silencing of the HPV E7 gene inhibited the growth of HPV-positive HNC cells and in vivo tumour load. We show that HPV E7 oncogene expression confers sensitivity to Alisertib on HNC cells where Alisertib-mediated loss in in vitro cell viability and in vivo tumour load is dependent on E7 expression. Moreover, Aurora kinase inhibition induced degradation of MCL-1 in HPV E7-expressing HNC cells.

CONCLUSION:

Overall, we show that Aurora kinases are a novel therapeutic target for HPV-positive HNCs. It might be feasible to combine Aurora kinase and MCL-1 inhibitors for future HNC therapies.

KEYWORDS:

Alisertib; Aurora kinase A; HPV E7; Head and neck cancer; Human papilloma virus

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