细胞周期蛋白依赖性激酶 9 (CDK9) 刺激癌症中的致癌转录途径，CDK9 抑制剂已成为有前途的治疗候选药物。在前列腺癌细胞系（异种移植小鼠模型）中评估了口服生物可利用的 CDK9 抑制剂 CDKI-73 的活性，以及患者来源的肿瘤外植体和类器官。通过挖掘公共数据集和免疫组织化学来评估临床标本中 CDK9 的表达。通过基于细胞的测定、分子分析和转录组/表观基因组方法确定 CDKI-73 对前列腺癌细胞的影响。在雄激素受体 (AR) 驱动的多种体外和体内模型中，CDKI-73 抑制增殖并增强细胞死亡和 AR 独立模型。从机制上讲，CDKI-73 介导的 RNA 聚合酶 II 丝氨酸 2 磷酸化抑制导致 BCL-2 抗凋亡因子表达减少和转录缺陷。转录组学和表观基因组学方法显示，CDKI-73 抑制 AR、MYC 和 BRD4 调节的信号通路，这些信号通路是前列腺癌转录失调的关键驱动因素，并重新编程了与癌症相关的超级增强子。后面的这些发现促使人们对 CDKI-73 与 BRD4 抑制剂 AZD5153 进行评估，这种组合在患者来源的类器官和体内具有协同作用。我们的工作表明，CDK9 抑制会破坏多种致癌途径，并将 CDKI-73 定位为一种有前途的治疗剂用于前列腺癌，特别是侵袭性、难治性亚型。© 2024。作者。

Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates.The activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry. Effects of CDKI-73 on prostate cancer cells were determined by cell-based assays, molecular profiling and transcriptomic/epigenomic approaches.CDKI-73 inhibited proliferation and enhanced cell death in diverse in vitro and in vivo models of androgen receptor (AR)-driven and AR-independent models. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of BCL-2 anti-apoptotic factors and transcriptional defects. Transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signaling pathways regulated by AR, MYC, and BRD4, key drivers of dysregulated transcription in prostate cancer, and reprogrammed cancer-associated super-enhancers. These latter findings prompted the evaluation of CDKI-73 with the BRD4 inhibitor AZD5153, a combination that was synergistic in patient-derived organoids and in vivo.Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.© 2024. The Author(s).