2. Academic Validation
  3. Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer

Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer

  • Sci Adv. 2025 Apr 25;11(17):eadu0847. doi: 10.1126/sciadv.adu0847.
Fu Gui 1,  Baishan Jiang 2,  Jie Jiang 2,  Zhixiang He 2,  Takuya Tsujino 1 3,  Tomoaki Takai 1 3,  Seiji Arai 4 5,  Celine Pana 6,  Jens Köllermann 7,  Gary Andrew Bradshaw 8,  Robyn Eisert 8,  Marian Kalocsay 9,  Anne Fassl 6,  Steven P Balk 4,  Adam S Kibel 1,  Li Jia 1
Affiliations

Affiliations

  • 1 Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Urology, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.
  • 4 Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
  • 5 Department of Urology, Gunma University Graduate School of Medicine, Gunma, Japan.
  • 6 Goethe University Frankfurt, University Hospital, Department of Urology, Frankfurt am Main, Germany.
  • 7 Goethe University Frankfurt, University Hospital, Dr. Senckenberg Institute of Pathology, Frankfurt am Main, Germany.
  • 8 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 9 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
PMID: 40267193 DOI: 10.1126/sciadv.adu0847
Abstract

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.

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