PLK1 Inhibitors and Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling

We found that synergy between the antiandrogen abiraterone and Plk1 inhibitors was completely independent of abiraterone's effects on AR signaling. To identify AR-independent effects of abiraterone we designed a comprehensive RNA seq experiment. This identified an AR-independent synergy-specific gene set signature that was induced by abiraterone treatment and was dominated by gene sets related to mitosis and the mitotic spindle. AR-independent effects of abiraterone were isolated by including an enzalutamide treatment arm and by utilizing cancer cell lines that do not express the AR. Synergy-specific gene expression changes were identified by using cell lines that responded synergistically or non-synergistically to combined abiraterone and onvansertib. Overall design: Prostate cancer cells that either did or did not respond synergistically to combined abiraterone and Plk1 inhibition treatment were treated with DMSO, abiraterone, enzalutamide, onvansertib, the abiraterone-onvansertib combination or the enzalutamide-onvansertib combination. Non-prostate cancer cells were treated with DMSO, abiraterone, onvansertib or the abiraterone-onvansertib combination. Gene expression was analyzed by RNA sequencing and data was transformed to gene set scores using Gene set variation analysis (GSVA).