BUB1B Mitotic Kinase Dependency Reveals CENP-E Inhibition as a Tractable Approach for Castration and Enzalutamide Resistant Prostate Cancer.

Abstract

Castration-resistant prostate cancer (CRPC) progression despite treatment with potent androgen receptor (AR) antagonists such as enzalutamide is a major clinical challenge. The mitotic kinase BUB1B is a central member of an oncogenic seven-gene network that drives CRPC. Here, we characterized BUB1B as an actionable therapeutic target for treatment-resistant PC. High BUB1B expression correlated with PC progression and aggressiveness. BUB1B depletion blocked CRPC cell proliferation through accumulation in G2/M and mitotic delay. Conversely, ectopic expression of BUB1B conferred castration and enzalutamide resistance to androgen-dependent PC cells in vitro and in vivo. BUB1B promotion of CRPC was not dependent on AR canonical signaling as assessed through AR knockdown and PROTAC-mediated AR degradation. BUB1B kinase activity was necessary for CRPC progression, as only wild type (WT), but not two kinase-dead mutants, promoted castration-resistant growth, and BUB1B kinase activity was required to maintain castration resistance. Expression of the primary substrate of BUB1B, CENP-E, also promoted CRPC progression, while a phosphodeficient mutant of the BUB1B phosphorylation site was ineffective. Moreover, only a phosphomimic mutant of CENP-E rescued growth after BUB1B depletion in CRPC cells, indicating that BUB1B-dependent phosphorylation of CENP-E was sufficient for progression and necessary to sustain CRPC growth. Targeting CENP-E with the clinically tested, small-molecule GSK923295 phenocopied BUB1B knockdown, sensitized resistant cells to enzalutamide and suppressed growth of enzalutamide-resistant xenografts in vivo. These data support BUB1B kinase as a driver of castration and enzalutamide resistance, positioning CENP-E inhibition as an attainable approach for treatment-resistant disease.