Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China.
Adv Sci (Weinh). 2023 Dec;10(36):e2302368. doi: 10.1002/advs.202302368. Epub 2023 Nov 10.
The development of castration-resistant prostate cancer (CRPC) is a significant factor that reduces life expectancy among patients with prostate cancer. Previously, it is reported that CDK4/6 inhibitors can overcome the resistance of CRPC to BET inhibitors by destabilizing BRD4, suggesting that the combination of CDK4/6 inhibitors and BET inhibitors is a promising approach for treating CRPC. In this study, candidates that affect the combined antitumor effect of CDK4/6 inhibitors and BET inhibitors on CRPC is aimed to examine. The data demonstrates that CBX3 is abnormally upregulated in CDK4/6 inhibitors-resistant cells. CBX3 is almost positively correlated with the cell cycle in multiple malignancies and is downregulated by BET inhibitors. Mechanistically, it is showed that CBX3 is transcriptionally upregulated by BRD4 in CRPC cells. Moreover, it is demonstrated that CBX3 modulated the sensitivity of CRPC to CDK4/6 inhibitors by binding with RB1 to release E2F1. Furthermore, it is revealed that PLK1 phosphorylated CBX3 to enhance the interaction between RB1 and CBX3, and desensitize CRPC cells to CDK4/6 inhibitors. Given that BRD4 regulates CBX3 expression and PLK1 affects the binding between RB1 and CBX3, it is proposed that a dual BRD4/PLK1 inhibitor can increase the sensitivity of CRPC cells to CDK4/6 inhibitors partially through CBX3.
去势抵抗性前列腺癌（CRPC）的发展是降低前列腺癌患者预期寿命的重要因素。先前有报道称，CDK4/6 抑制剂可以通过使 BRD4 不稳定来克服 CRPC 对 BET 抑制剂的耐药性，这表明 CDK4/6 抑制剂和 BET 抑制剂的联合使用是治疗 CRPC 的一种很有前途的方法。在本研究中，旨在研究影响 CDK4/6 抑制剂和 BET 抑制剂联合抗肿瘤作用的候选药物。数据表明，CBX3 在 CDK4/6 抑制剂耐药细胞中异常上调。在多种恶性肿瘤中，CBX3 与细胞周期几乎呈正相关，并且被 BET 抑制剂下调。从机制上讲，CBX3 在 CRPC 细胞中被 BRD4 转录上调。此外，研究表明 CBX3 通过与 RB1 结合释放 E2F1 来调节 CRPC 对 CDK4/6 抑制剂的敏感性。此外，研究表明 PLK1 磷酸化 CBX3 以增强 RB1 和 CBX3 之间的相互作用，并使 CRPC 细胞对 CDK4/6 抑制剂脱敏。鉴于 BRD4 调节 CBX3 的表达，PLK1 影响 RB1 和 CBX3 之间的结合，因此建议双重 BRD4/PLK1 抑制剂可以通过 CBX3 部分增加 CRPC 细胞对 CDK4/6 抑制剂的敏感性。
