Targeting Plk1 to enhance efficacy of Olaparib in castration-resistant prostate cancer

Abstract

Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of Olaparib in 22RV1, a BRCA1 deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with Olaparib results in an override of the G1/S checkpoint, leading to high expression of Plk1, which attenuates Olaparib’s overall efficacy. In BRCA1 wild type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of Olaparib in the presence of p53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA-mutant patient subgroups who might also respond favorably to PARPi.