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

Brian Gabrielli1, Fawzi Bokhari2, Max V Ranall2

  • 1The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. brianG@uq.edu.au n.mcmillan@griffith.edu.au.

Molecular Cancer Therapeutics
|October 31, 2015
PubMed

Insights

Targeting Aurora kinase A (AURKA) with Alisertib shows promise as a curative therapy for human papillomavirus (HPV)-driven cancers. This investigational drug selectively induces apoptosis in HPV-positive cancer cells, leading to tumor regression.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • Human papillomavirus (HPV) drives cervical cancer through oncogenes like E7.
  • Cancers driven by HPV oncogenes exhibit addiction to these specific drivers.
  • Aurora kinase A (AURKA) inhibition is synthetically lethal with HPV E7 expression.

Purpose of the Study:

  • To investigate the efficacy of AURKA inhibition using MLN8237/Alisertib in HPV-driven cancers.
  • To elucidate the mechanism of action of Alisertib in HPV-positive cancer cells.
  • To evaluate Alisertib's therapeutic potential in preclinical cancer models.

Main Methods:

  • Screening of the human kinome to identify synthetic lethality with HPV E7.
  • Treatment of HPV-positive cancer cell lines and xenografts with Alisertib.
  • Analysis of apoptosis, mitotic delay, and protein levels (Mcl-1, BIM).
  • Assessment in a transgenic model of premalignant HPV-driven disease.

Main Results:

  • Alisertib selectively promoted apoptosis in HPV cancers via extended mitotic delay.
  • Mitotic delay reduced Mcl-1 and increased BIM levels, dependent on HPV E7 expression.
  • Alisertib inhibited xenograft growth; HPV xenografts showed regression and no regrowth.
  • Transgenic models of premalignant HPV-driven disease were sensitive to Alisertib.

Conclusions:

  • Targeting AURKA with Alisertib offers a potential curative therapy for HPV-driven cancers.
  • Alisertib demonstrates significant efficacy in preclinical models, including complete tumor regression.
  • This approach represents a novel therapeutic strategy for HPV-associated malignancies.

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