Polo-like kinase-1 Inhibitors and the Antiandrogen Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling

Abstract

ABSTRACTAbiraterone, a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC), slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). We report that inhibitors of the mitotic kinase Plk1, including the clinically active third-generation Plk1 inhibitor onvansertib, when co-administered with abiraterone, synergistically kill cancer cells from a wide variety of tumor types in an androgen-independent manner, both in vitro and in vivo. Abiraterone treatment alone results in defects in mitotic spindle orientation, failure of complete chromosome condensation, and upregulation of mitosis and mitotic-spindle related gene sets independently of its effects on AR signaling. These effects, while mild following abiraterone monotherapy, result in profound sensitization to the anti-mitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cell death and entosis. In a murine PDX model of mCRPC, combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared to either agent alone.STATEMENT OF SIGNIFICANCEA phase 2 clinical trial is underway (NCT03414034) testing combined Plk1 inhibitor onvansertib and abiraterone in mCRPC patients with nascent abiraterone resistance. Our work establishes a mechanistic basis for that trial and indicates that combined abiraterone and onvansertib co-treatment may have broad utility for cancer treatment beyond mCRPC.