Targeting CBX3 by a dual BET/PLK1 inhibitor enhances the anti-tumor efficacy of CDK4/6 inhibitors in prostate cancer

Castration-resistant prostate cancer (CRPC) after commencement of Androgen deprivation therapy (ADT) seriously shorten the life span of patients with prostate cancer. The BET inhibitors and CDK4/6 inhibitors have shown efficacy in preclinical models of prostate cancer. We previously reported that CDK4/6 inhibitors overcome the resistance of CRPC to BET inhibitors by destabilizing BRD4, which indicates that the combination of CDK4/6 inhibitors and BET inhibitors is also promising for the treatment of CRPC. In this study, we attempted to exploit the candidates affecting the antitumor activity of CDK4/6 inhibitors and BET inhibitors in CRPC. Our data demonstrated that CBX3 is almost positively correlated with the cell cycle of multiple malignancies and is downregulated by BET inhibitors. Then, we showed that CBX3 is transcriptionally upregulated by BRD4 in CRPC cells. Moreover, we demonstrated that CBX3 modulates the sensitivity of CRPC to CDK4/6 inhibitors through binding with RB1 to release E2F1. Furthermore, we revealed that PLK1 phosphorylates CBX3 to enhance the interaction between RB1 and CBX3, and desensitized CRPC cells to CDK4/6 inhibitors. Given that BRD4 regulates CBX3 expression and PLK1 affects the binding between RB1 and CBX3, we proposed that a dual BRD4/PLK1 inhibitor could increase the sensitivity to CDK4/6 inhibitors partially through CBX3 in CRPC cells.