TY - JOUR
T1 - CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer
AU - Rahman, Razia
AU - Rahaman, Muhammed H.
AU - Hanson, Adrienne R.
AU - Choo, Nicholas
AU - Xie, Jianling
AU - Townley, Scott L.
AU - Shrestha, Raj
AU - Hassankhani, Ramin
AU - Islam, Saiful
AU - Ramm, Susanne
AU - Simpson, Kaylene J.
AU - Risbridger, Gail P.
AU - Best, Giles
AU - Centenera, Margaret M.
AU - Balk, Steven P.
AU - Kichenadasse, Ganessan
AU - Taylor, Renea A.
AU - Butler, Lisa M.
AU - Tilley, Wayne D.
AU - Conn, Simon J.
AU - Lawrence, Mitchell G.
AU - Wang, Shudong
AU - Selth, Luke A.
PY - 2024/10/5
Y1 - 2024/10/5
N2 - 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.
AB - 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.
KW - Drug development
KW - Oncogenes
KW - Prostate cancer
KW - Targeted therapies
UR - http://www.scopus.com/inward/record.url?scp=85200986340&partnerID=8YFLogxK
U2 - 10.1038/s41416-024-02810-8
DO - 10.1038/s41416-024-02810-8
M3 - Article
AN - SCOPUS:85200986340
SN - 0007-0920
VL - 131
SP - 1092
EP - 1105
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 6
ER -
