Inhibition of the Cyclin K‐CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer

• Published in: International journal of cancer 2024-03, Vol.154 (6), p.1082-1096
• Main Authors: Frei, Katharina, Schecher, Sabrina, Daher, Tamas, Hörner, Nina, Richter, Jutta, Hildebrand, Ute, Schindeldecker, Mario, Witzel, Hagen R., Tsaur, Igor, Porubsky, Stefan, Gaida, Matthias M., Roth, Wilfried, Tagscherer, Katrin E.
• Format: Article
• Language: English
• Subjects: Androgen Antagonists - pharmacology; Androgen Antagonists - therapeutic use; androgen deprivation therapy; Androgens; Anilides; Apoptosis; Biomarkers; Cancer; Cell culture; Cyclin K‐CDK12 complex; Cyclin-Dependent Kinases; Cyclins - genetics; DNA Damage; DNA repair; Endocrine therapy; Humans; Immunohistochemistry; Male; Medical research; Patients; Prostate; Prostate cancer; Prostate carcinoma; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Pyrimidines; Retrospective Studies; Targeted cancer therapy; THZ531; Tissue culture
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.34778

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. What's new? The recurrence of prostate cancer (PCa) following androgen deprivation therapy (ADT) is associated with treatment resistance. A promising avenue for overcoming resistance involves targeted inhibition of CycK‐CDK12, a complex that serves a critical role in PCa cell survival. The present study, using an ex vivo PCa tissue culture model, shows that THZ531, a covalent CDK12/13 inhibitor, increases the responsiveness of androgen‐sensitive PCa cells to ADT and exerts anti‐proliferative, pro‐apoptotic activity. Meanwhile, more aggressive PCa was correlated with CycK expression. The findings highlight the clinical relevance of CDK12 inhibition and CycK expression, opening new prognostic and therapeutic opportunities for PCa.