Bub1B Mitotic Kinase Drives Therapy Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) that progresses despite treatment with potent AR antagonists such as enzalutamide is a major clinical problem. Through an unbiased systems biology approach, we previously identified a therapeutically relevant seven gene set that drives CRPC. The mitotic checkpoint kinase, BUB1B (BUBR1) is a key member of this gene set, and we report here that BUB1B is a tractable and promising new therapeutic target in aggressive, treatment-resistant PC. We found that high BUB1B expression is correlated with PC progression and aggressiveness. In established CRPC cells, BUB1B depletion blocked cell proliferation through cell cycle arrest and mitosis delay. Ectopic expression of BUB1B, at levels found in CRPC, conferred castration-resistant growth of androgen-dependent PC cells in vitro and in vivo. We showed that BUB1B kinase activity was essential for CRPC progression, as only wild type (wt) BUB1B and neither of two kinase-dead mutants promoted castration-resistant growth of androgen-dependent PC cells. Rescue experiments with wt or kinase-dead mutants showed further that BUB1B kinase activity was also required to maintain proliferation of established CRPC cells. While persistent androgen receptor (AR) signaling is a mechanism of CRPC progression, BUB1B promotion of CRPC was not dependent on AR as assessed through AR knockdown. Consistent with an AR-bypass mechanism, ectopic expression of BUB1B rendered PC cells resistant to enzalutamide in vitro and in vivo. Our data points to BUB1B as a key driver of CRPC progression and enzalutamide resistance and suggests that targeting BUB1B kinase is a promising therapeutic approach for lethal, treatment-resistant disease. Statement of significanceWe document a novel role for BUB1B kinase as a critical driver of castration- and enzalutamide-resistant prostate cancer, highlighting the therapeutic potential of BUB1B kinase inhibition to overcome lethal treatment-resistant disease.