Targeting Aurora A Kinase (AAK) in Platinum-Resistant High Grade Serous Ovarian Cancer.

Ram N Ganapathi,Ashley P Sutker,Mahrukh K Ganapathi,Kaitlin E Klotz,Eric J Norris

doi:10.3389/fonc.2020.01354

Ram N Ganapathi, Ashley P Sutker + Show 3 more

Open Access

https://doi.org/10.3389/fonc.2020.01354

Copy DOI

Abstract

Aurora A kinase (AAK) involved in G2-M transition is functionally involved in centrosome maturation and maintaining an active spindle assembly checkpoint. We tested the hypothesis that in platinum-taxane resistant high grade serous ovarian cancer (HGSOC) inhibition of AAK involved in G2-M transition would enhance the anti-tumor activity of cisplatin (CP) or paclitaxel (PT). Using HGSOC cell lines from platinum-taxane refractory patients that do not harbor BRCA1/2 mutations, we tested the anti-tumor activity of CP, or PT alone or in combination with the AAK inhibitor alisertib (AL). Treatment with CP for 3 h or PT for 6 h followed sequentially by AL for 48 h led to a significant decrease in cell survival (p < 0.001) compared to treatment with either drug alone in HGSOC cells but not in immortalized normal human ovarian surface epithelium or normal human fallopian tube secretory epithelium cells. The treatment with CP or PT followed by AL also led to a significant increase in reactive oxygen species (p < 0.05), apoptosis (p < 0.001) and accumulation of cells in G2/M that was accompanied by a modest increase in expression of AAK. Downregulation of AAK, but not aurora B kinase, with targeted siRNAs also significantly enhanced apoptosis by CP or PT, suggesting that AL specifically targeted AAK. In summary, in HGSOC without BRCA1/2 mutations, CP, or PT resistance can potentially be circumvented by sequential treatment with AL that inhibits AAK involved in G2-M transition.

Highlights

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and comprises various distinct subtypes that differ in genetic drivers, histologic features, and clinical outcome [1]
Using cell culture models of recurrent High-grade serous ovarian carcinoma (HGSOC) without BRCA mutations that were established from patients clinically refractory to platinum/taxane therapy, we demonstrate that the efficacy of AL treatment with CP or PT which is sequence dependent, results in enhanced growth inhibition, generation of reactive oxygen species (ROS), increased accumulation of cells in G2/M phase and apoptosis in tumor compared to normal cells
In HGSOC cell lines without BRCA1/BRCA2 mutations from patients clinically refractory to platinum/taxane treatment we demonstrate that following CP or PT treatment the sequential use of the Aurora A kinase (AAK) inhibitor AL at clinically achievable drug concentrations [26] leads to synergistic cell kill

Summary

Introduction

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and comprises various distinct subtypes that differ in genetic drivers, histologic features, and clinical outcome [1]. Response rates to second-line therapy decreases with each recurrence due to the development of drug resistance [2, 3]. Several studies have investigated the molecular basis of chemoresistance to platinum/taxane chemotherapy in HGSOC, few effective treatment strategies have been identified or validated for use in clinical practice. For patients with BRCA1/2 mutations or homologous recombination deficiency (HRD), personalized second-line treatment strategies with inhibitors of Aurora A Kinase Platinum Resistance and HGSOC poly (adenosine diphosphate ribose) polymerase (PARP) has resulted in remarkable enhancement of disease-free survival [4]. In the absence of BRCA1/BRCA2 mutations or HRD in recurrent HGSOC, strategies that manipulate the DNA damage checkpoint or G2-M transition could help alleviate drug resistance

Methods

Results

Conclusion