CDK9 inhibition constrains multiple oncogenic transcriptional and epigenetic pathways in prostate cancer
- Author(s)
- Rahman, R; Rahaman, MH; Hanson, AR; Choo, N; Xie, J; Townley, SL; Shrestha, R; Hassankhani, R; Islam, S; Ramm, S; Simpson, KJ; Risbridger, GP; Best, G; Centenera, MM; Balk, SP; Kichenadasse, G; Taylor, RA; Butler, LM; Tilley, WD; Conn, SJ; Lawrence, MG; Wang, S; Selth, LA;
- Journal Title
- British Journal of Cancer
- Publication Type
- Research article
- 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.
- Publisher
- Springer Nature
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1038/s41416-024-02810-8
- Open Access at Publisher's Site
https://doi.org/10.1038/s41416-024-02810-8- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-09-19 04:50:55
Last Modified: 2025-01-28 06:44:44