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- Title
CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer.
- Authors
Rahman, Razia; Rahaman, Muhammed H.; Hanson, Adrienne R.; Choo, Nicholas; Xie, Jianling; Townley, Scott L.; Shrestha, Raj; Hassankhani, Ramin; Islam, Saiful; Ramm, Susanne; Simpson, Kaylene J.; Risbridger, Gail P.; Best, Giles; Centenera, Margaret M.; Balk, Steven P.; Kichenadasse, Ganessan; Taylor, Renea A.; Butler, Lisa M.; Tilley, Wayne D.; Conn, Simon J.
- Abstract
Background: Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates. Methods: The activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry. Effects of CDKI-73 on prostate cancer cells were determined by cell-based assays, molecular profiling and transcriptomic/epigenomic approaches. Results: CDKI-73 inhibited proliferation and enhanced cell death in diverse in vitro and in vivo models of androgen receptor (AR)-driven and AR-independent models. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of BCL-2 anti-apoptotic factors and transcriptional defects. Transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signaling pathways regulated by AR, MYC, and BRD4, key drivers of dysregulated transcription in prostate cancer, and reprogrammed cancer-associated super-enhancers. These latter findings prompted the evaluation of CDKI-73 with the BRD4 inhibitor AZD5153, a combination that was synergistic in patient-derived organoids and in vivo. Conclusion: Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
- Publication
British Journal of Cancer, 2024, Vol 131, Issue 6, p1092
- ISSN
0007-0920
- Publication type
Article
- DOI
10.1038/s41416-024-02810-8