Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer
Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained "BRCAness" state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including both in vitro and in vivo CRPC models, demonstrate that BSJ-5-63 exerts potent antitumor activity in both AR-positive and AR-negative setting. This study introduces BSJ-5-63 as a promising therapeutic agent that addresses both DNA repair and AR signaling mechanisms, with potential benefits for a board patient population.
Authors
- Jie Jiang (ORCID: https://orcid.org/0000-0003-3795-672X)
- Takuya Tsujino (ORCID: https://orcid.org/0000-0003-1559-1889)
- Tomoaki Takai (ORCID: https://orcid.org/0000-0002-5138-939X)
- Jens W. Köllermann (ORCID: https://orcid.org/0000-0001-8495-6621)
- Gary A. Bradshaw (ORCID: https://orcid.org/0000-0001-9724-6100)
- Fu Gui (ORCID: https://orcid.org/0000-0001-8329-7118)
- Baishan Jiang (ORCID: https://orcid.org/0000-0001-6796-9500)
- Anne Fassl (ORCID: https://orcid.org/0000-0003-2777-0585)
- Robyn J. Eisert (ORCID: https://orcid.org/0000-0001-7977-249X)
- Seiji Arai (ORCID: https://orcid.org/0000-0002-9514-735X)
- Adam S. Kibel (ORCID: https://orcid.org/0000-0002-9446-7781)
- Zhixiang He (ORCID: https://orcid.org/0000-0002-4493-0336)
- Marian Kalocsay (ORCID: https://orcid.org/0000-0002-4187-5829)
- Steven P. Balk (ORCID: https://orcid.org/0000-0002-4546-7371)
- Celine Pana
- Jia Li (ORCID: https://orcid.org/0000-0003-4017-1157)
Institutions
- Goethe University Frankfurt (DE)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Harvard University (US)
- Gunma University (JP)
- Dana-Farber Cancer Institute (US)
- Center for Systems Biology (US)
- Osaka University of Pharmaceutical Sciences (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1126/sciadv.adu0847
- Citations
- 9
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 9.41