Withdrawn 36th Lorne Cancer Conference 2024

CDK9 inhibition as a therapeutic strategy in advanced prostate cancer (NOT ATTENDING) (#134)

Razia Rahman 1 , Muhammed H. Rahaman 2 , Adrienne R. Hanson 1 3 , Jianling Xie 1 3 , Scott L. Townley 1 3 , Nicholas Choo 4 5 , Kaylene J. Simpson 6 7 8 , Susanne Ramm 7 8 , Ganessan Kichenadasse 1 , Simon J. Conn 1 , Gail P. Risbridger 4 5 , Renea A. Taylor 4 5 , Mitchell G. Lawrence 4 5 , Wayne D. Tilley 9 10 , Margaret M. Centenera 10 11 12 , Lisa M. Butler 10 11 12 , Shudong Wang 2 , Luke A. Selth 1 3
  1. Flinders Health and Medical Research Institute and Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, SA, Australia
  2. Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
  3. Freemasons Centre for Male Health and Wellbeing, Flinders University, Bedford Park, SA, Australia
  4. Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, VIC, Australia
  5. Prostate Cancer Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  6. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  7. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  8. Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC, Australia
  9. Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
  10. Freemasons Centre for Male Health and Wellbeing, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
  11. South Australian Health and Medical Research Institute, Adelaide, SA, Australia
  12. South Australian immunoGENomics Cancer Institute (SAiGENCI), University of Adelaide, Adelaide, SA, Australia

Prostate cancer is the most frequently diagnosed non-skin cancer and a leading cause of cancer-related death in men worldwide. The key driver of prostate cancer is the androgen receptor (AR); thus, AR-targeted therapies are the primary treatment strategy for metastatic prostate cancer. While most men initially respond to AR-targeted therapies, they are not always curative and patients inevitably progress to a highly aggressive and lethal disease state termed castration-resistant prostate cancer (CRPC). Therefore, the development of new and effective treatment options for CRPC is essential to improve patient outcomes. 

A plausible therapeutic target in CRPC is cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation by phosphorylating RNA polymerase II. Dysregulated transcriptional activity due to elevated CDK9 activity has been observed in various haematological and solid cancers, and CDK9 inhibitors are now being investigated in clinical trials. In this study, we describe the efficacy of a novel and orally bioavailable CDK9 inhibitor, CDKI-73, in prostate cancer. CDKI-73 potently inhibits proliferation in a range of prostate cancer cell lines representing distinct CRPC subtypes and causes cell death by apoptosis. CDKI-73 was also found to be highly effective in more clinically relevant systems, including patient-derived organoids, patient-derived tumour explants and mouse xenografts. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of anti-apoptotic factors and defects in overall transcription. Moreover, transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signalling pathways regulated by AR, MYC and BRD4, which are key drivers of dysregulated transcription in prostate cancer, and led to reprogramming of 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. Collectively, our evaluation provides new insights into CDK9’s oncogenic activity and reveals CDKI-73 as a promising therapeutic agent for prostate cancer.