Abstract 5715: Enhancing PARP inhibitor efficacy with CDK12/7/9 degradation in prostate cancer

Abstract Current treatments for advanced prostate cancer (PCa) mainly target the androgen receptor (AR) signaling pathway. However, the development of castration-resistant prostate cancer (CRPC) and resistance to AR signaling inhibitors remains a significant clinical challenge.In recent years, the FDA has approved four PARP inhibitors (PARPis) - olaparib, rucaparib, talazoparib, and niraparib - either as monotherapy or in combination with AR signaling inhibitors for CRPC patients carrying deleterious germline or somatic BRCA1/2 mutations or other homologous recombination repair (HRR) gene mutations. CDK12, a kinase associated with the phosphorylation of the carboxy-terminal domain of RNA polymerase II, is crucial for the transcriptional processivity of long mRNA transcripts, including key HRR genes such as BRCA1 and BRCA2. CDK12 alterations, primarily biallelic truncating mutations, have been identified in 5-7% of PCa cases. In this study, we demonstrate that acute CDK12 loss results in BRCA1/2 downregulation and sensitizes CRPC cells to PARP inhibition. However, this sensitization is absent in CRPC adapted to chronic CDK12 loss, where BRCA1/2 expression is restored. Furthermore, degradation of CDK12/7/9 enhances the synthetic lethality of PARP inhibition through acute induction of a "BRCAness" state and AR signaling suppression in PCa. We developed BSJ-5-63, a CDK12/7/9 proteolysis-targeting chimera (PROTAC) degrader, which effectively degrades CDK12 to induce an acute "BRCAness" state, sensitizing cancer cells to PARP inhibitors regardless of their HRR status. In addition, BSJ-5-63 degrades CDK7/9, attenuating AR signaling and further promoting the synthetic lethality of PARP inhibition.Acute CDK12/7/9 degradation by BSJ-5-63 exhibits potent anti-tumor effects in both in vitro and in vivo CRPC models. This study introduces BSJ-5-63 as a promising therapeutic agent that targets both DNA repair and AR signaling pathways, offering potential benefits for a broad patient population. Citation Format: Fu Gui, Baishan Jiang, Jie Jiang, Marian Kalocsay, Anne Fassl, Steven P. Balk, Adam S. Kibel, Li Jia. Enhancing PARP inhibitor efficacy with CDK12/7/9 degradation in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5715.