Inhibition of Aurora A and Aurora B Is Required for the Sensitivity of HPV-Driven Cervical Cancers to Aurora Kinase Inhibitors.

David Martin,Brian Gabrielli,Alexander Stevenson,Nigel Mcmillan,Martina Proctor,Lewis Perrin,Sora Fallaha

doi:10.1158/1535-7163.mct-17-0159

Abstract

The activity and efficacy of Aurora inhibitors have been reported in a wide range of cancer types. The most prominent Aurora inhibitor is alisertib, an investigational Aurora inhibitor that has been the subject of more than 30 clinical trials. Alisertib has inhibitory activity against both Aurora A and B, although it is considered to be primarily an Aurora A inhibitor in vivo Here, we show that alisertib inhibits both Aurora A and B in vivo in preclinical models of HPV-driven cervical cancer, and that it is the inhibition of Aurora A and B that provides the selectivity and efficacy of this drug in vivo in this disease setting. We also present formal evidence that alisertib requires progression through mitosis for its efficacy, and that it is unlikely to combine with drugs that promote a G2 DNA damage checkpoint response. This work demonstrates that inhibition of Aurora A and B is required for effective control of HPV-driven cancers by Aurora kinase inhibitors. Mol Cancer Ther; 16(9); 1934-41. ©2017 AACR.

Highlights

Aurora kinases are critical regulators of entry into and exit from mitosis
We have previously reported the identification of Aurora A and Aurora B as synthetic lethal targeting with oncogenic HPV-E7 expression and validated this in vitro and in vivo using the Aurora A inhibitor MLN8237/alisertib [9]
One of the features of alisertib was the modest delay in mitosis and failed cytokinesis found in all cell types, the delay was increased 3- to 5-fold in the HPV-driven tumor lines [9]

Summary

Introduction

Aurora kinases are critical regulators of entry into and exit from mitosis. Aurora B regulates mitotic exit by signaling correct microtubule attachments to the kinetochore and is a component of the chromosomal passenger complex which controls correct partitioning of the replicated genome at anaphase and cytokinesis [1]. Many of the drugs developed have activity toward all of the Aurora kinases, Aurora A and B appear to be the primary kinases overexpressed and involved in cancer development [3]. These inhibitors disrupt mitosis, and the mitotic catastrophe resulting from Aurora inhibitor treatment is thought to be a primary target for this class of drugs [4]. It has been reported in melanoma that a primary outcome of Aurora kinase inhibition was senescence, this appeared to be cell line dependent [5,6,7,8]

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Results

Conclusion