雄激素剥夺疗法（ADT）是当前晚期前列腺癌（PCa）患者一线治疗理念的支柱。然而，由于治疗失败和复发，迫切需要研究新的靶向治疗方法。在本研究中，我们使用新型共价 CDK12/13 抑制剂 THZ531 研究了 Cyclin K-CDK12 复合物作为 PCa 新型治疗方法的适用性。在这里，我们发现 THZ531 会损害 PCa 细胞系中的细胞增殖、诱导细胞凋亡并降低选定的 DNA 修复基因的表达，这与 DNA 损伤程度的增加有关。此外，THZ531 和 ADT 的组合可增强雄激素敏感 PCa 细胞的抗肿瘤作用。 THZ531 与 ADT 组合的抗增殖和促凋亡活性在离体 PCa 组织培养模型中得到验证。在对 300 个临床组织样本的回顾性免疫组织化学分析中，我们发现细胞周期蛋白 K (CycK) 而非 CDK12 表达与更具侵袭性的 PCa 类型相关。总之，本研究证明了 CycK-CDK12 复合物作为 PCa 与 ADT 联合治疗的有希望的靶标的临床相关性，及其作为 PCa 患者预后生物标志物的重要性。© 2023 作者。约翰·威利出版的《国际癌症杂志》

Androgen deprivation therapy (ADT) is the mainstay of the current first-line treatment concepts for patients with advanced prostate carcinoma (PCa). However, due to treatment failure and recurrence investigation of new targeted therapeutics is urgently needed. In this study, we investigated the suitability of the Cyclin K-CDK12 complex as a novel therapeutic approach in PCa using the new covalent CDK12/13 inhibitor THZ531. Here we show that THZ531 impairs cellular proliferation, induces apoptosis, and decreases the expression of selected DNA repair genes in PCa cell lines, which is associated with an increasing extent of DNA damage. Furthermore, combination of THZ531 and ADT leads to an increase in these anti-tumoral effects in androgen-sensitive PCa cells. The anti-proliferative and pro-apoptotic activity of THZ531 in combination with ADT was validated in an ex vivo PCa tissue culture model. In a retrospective immunohistochemical analysis of 300 clinical tissue samples we show that Cyclin K (CycK) but not CDK12 expression correlates with a more aggressive type of PCa. In conclusion, this study demonstrates the clinical relevance of the CycK-CDK12 complex as a promising target for combinational therapy with ADT in PCa and its importance as a prognostic biomarker for patients with PCa.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.