Abstract 973: The selective polo-like kinase (Plk1) inhibitor onvansertib and the antiandrogen abiraterone synergistically kill cancer cells through disruption of mitosis independently of androgen receptor signaling
Authors: Patterson Jesse C. , Croucher Peter J. , Ridinger Maya , Einstein David J. , Varkaris Andreas , Balk Steven P. , Bubley Glenn J. , Erlander Mark G. , Yaffe Michael B. 
Published: July 2021

Abiraterone acetate, a widely-used standard of care for metastatic castrate-resistant prostate cancer (mCRPC), both abrogates androgen synthesis and inhibits the androgen receptor (AR). The AR is a central driver of prostate cancer, and abiraterone slows disease progression in the majority of men, however, extended treatment universally results in acquired resistance. We have observed that Plk1 inhibitors (Plk1i), including the clinically active, highly-selective and orally available Plk1i onvansertib, synergize with abiraterone in models of CRPC, providing a potential means to reverse or delay the onset of abiraterone resistance. Plk1 is a serine/threonine kinase that regulates entry into and progression through mitosis. In contrast to abiraterone, the AR-antagonist enzalutamide does not synergistically kill CRPC cells in combination with Plk1i. Moreover, we have found Plk1i-abiraterone synergy in AR-negative cancer cells demonstrating that this synergy is AR independent. A phase 2 clinical trial (NCT03414034) is currently testing combination of onvansertib and abiraterone in mCRPC patients with nascent abiraterone resistance. Preliminary efficacy, as measured by PSA decline or stabilization, was observed in a subset of patients, including those harboring the AR splice variant 7.

To identify the mechanisms driving Plk1i-abiraterone synergy, prostate cancer cell lines showing, or not showing, synergy between these drugs (referred to as synergistic or non-synergistic cells, respectively), were treated with vehicle, abiraterone, enzalutamide, or onvansertib prior to RNA sequencing and Gene Set Variation Analysis (GSVA).

In synergistic cells, a group of mitosis and mitotic spindle related gene sets were significantly upregulated by both abiraterone and onvansertib. These gene sets were not upregulated in non-synergistic cells, or by enzalutamide, indicating that abiraterone may target mitosis related genes or processes in an AR-independent manner. Live-cell microscopy showed that, while abiraterone does not cause gross mitotic arrest, it does impair mitotic spindle assembly. These mitotic gene sets were also relatively upregulated in untreated synergistic cells, suggesting that synergistic responses reflect baseline differences in molecular pathways.

In summary, we have found that abiraterone impacts spindle assembly and sensitizes some cancer cells to Plk1i resulting in synergistic mitotic arrest and spindle assembly checkpoint dependent cell death. Baseline differences in these processes may predict synergy and be predicative of patient responses to the onvansertib + abiraterone combination. This hypothesis is being evaluated in patients currently enrolled in the clinical study of onvansertib + abiraterone.

Citation Format: Jesse C. Patterson, Peter J. Croucher, Maya Ridinger, David J. Einstein, Andreas Varkaris, Steven P. Balk, Glenn J. Bubley, Mark G. Erlander, Michael B. Yaffe. The selective polo-like kinase (Plk1) inhibitor onvansertib and the antiandrogen abiraterone synergistically kill cancer cells through disruption of mitosis independently of androgen receptor signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 973.