Acute BRCAness Induction and AR Signaling Blockage through CDK12/7/9 Degradation Enhances PARP Inhibitor Sensitivity in Prostate Cancer.
Fu GuiBaishan JiangJie JiangZhixiang HeTakuya TsujinoTomoaki TakaiSeiji AraiCeline PanaJens KöllermannGary Andrew BradshawRobyn EisertMarian KalocsayAnne FasslSteven P BalkAdam S KibelLi JiaPublished in: bioRxiv : the preprint server for biology (2024)
This study introduces BSJ-5-63, a triple degrader designed to target CDK12, CDK7, and CDK9, making a significant advancement in CRPC therapy. The distinctive mechanism of BSJ-5-63 involves downregulating HRR genes and inhibiting AR signaling, thereby inducing a BRCAness state. This enhances sensitivity to PARP inhibition, effectively addressing ARSI resistance and improving the overall efficacy of treatment. The development of BSJ-5-63 represents a promising therapeutic approach, with the potential to benefit a broad spectrum of CRPC patients.
Keyphrases
- cell cycle
- prostate cancer
- end stage renal disease
- dna damage
- dna repair
- ejection fraction
- newly diagnosed
- chronic kidney disease
- liver failure
- radical prostatectomy
- prognostic factors
- signaling pathway
- cell proliferation
- peritoneal dialysis
- gene expression
- stem cells
- genome wide
- oxidative stress
- intensive care unit
- respiratory failure
- bone marrow
- acute respiratory distress syndrome
- genome wide analysis
- genome wide identification
- chemotherapy induced