ArticleScience advances2025
Acute BRCAness induction and AR pathway blockage through CDK12/7/9 degradation enhances PARP inhibitor sensitivity in prostate cancer.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Dual Compartmentalization of GSTA4 Suppresses Ferroptosis to Drive Antiandrogen Resistance in Prostate Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Expanding Synthetic Lethality in DNA Damage Response-Defective Cancers Through Stress Phenotype-Guided Kinase Targeting.International journal of molecular sciences · 2026Review
- Bipolar Androgen Therapy as a Potential Mechanistic Bridge to Enhance PARP Inhibitor Efficacy in Prostate Cancer.The Kaohsiung journal of medical sciences · 2026Article
- MNAT1 in gastrointestinal cancers: mechanistic insights and therapeutic strategies-a narrative review.Journal of gastrointestinal oncology · 2026Review
- Defective microhomology-mediated end joining inScience advances · 2026Article
- Mepce Restrains Ferroptosis in Prostate Cancer Through 7SK-P-TEFb Pause Control.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- CDK10 loss primes tumor cells for transcriptional vulnerability and sensitizes to CDK12/13 inhibition.Cell death & disease · 2026Article
- Phosphorylation of RBM39 by CDK13 stabilizes RAD50 mRNA to drive cisplatin resistance in endometrial cancer.The Journal of biological chemistry · 2026Article
- Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance.Pharmaceutics · 2026Review
- CDK9 degrader induces BRCAness and sensitizes castration-resistant prostate cancer to PARP inhibitor.Theranostics · 2026Article
- Defective Microhomology-Mediated End-joining in SMARCB1-Deficient Tumors.bioRxiv : the preprint server for biology · 2025Article
- Loss of CFIm activates YAP/TAZ and connects mRNA cleavage and polyadenylation inhibition to BRCAness.bioRxiv : the preprint server for biology · 2025Article
- Advancing Poly (ADP-ribose) Polymerase Inhibition Strategies BeyondJCO precision oncology · 2025Article
- Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders.Angewandte Chemie (International ed. in English) · 2025Article
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Authors and funding
16 authors.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.