CDK9 inhibition constrains multiple oncogenic transcriptional and epigenetic pathways in prostate cancer
Razia Rahman, Muhammed H. Rahaman, Adrienne R. Hanson, Nicholas Choo, Jianling Xie, Scott L. Townley, Raj K. Shrestha, Ramin Hassankhani, Saiful Islam, Susanne Ramm, Kaylene J. Simpson, Gail P. Risbridger, Giles Best, Margaret M. Centenera, Steven P. Balk, Ganessan Kichenadasse, Renea A. Taylor, Lisa M. Butler, Wayne D. Tilley, Simon J. Conn, Mitchell G. Lawrence, Shudong Wang, Luke A. Selth
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.