CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer.

Autor:	Rahman R; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia., Rahaman MH; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia., Hanson AR; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia., Choo N; Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia., Xie J; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia., Townley SL; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia., Shrestha R; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia.; Flinders University, Freemasons Centre for Male Health and Wellbeing, Bedford Park, SA, Australia., Hassankhani R; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia., Islam S; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia., Ramm S; Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia., Simpson KJ; Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, VIC, Australia., Risbridger GP; Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Cabrini Institute, Cabrini Health, Malvern, Melbourne, VIC, Australia.; Melbourne Urological Research Alliance (MURAL), Monash Biomedicine Discovery Institute Cancer Program, Monash University, Clayton, VIC, Australia., Best G; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia., Centenera MM; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia., Balk SP; Beth Israel Deaconess Medical Center, Boston, MA, USA., Kichenadasse G; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia.; Department of Medical Oncology, Flinders Medical Centre, Southern Adelaide Local Health Network, Adelaide, SA, South Australia., Taylor RA; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Cabrini Institute, Cabrini Health, Malvern, Melbourne, VIC, Australia.; Melbourne Urological Research Alliance (MURAL), Monash Biomedicine Discovery Institute Cancer Program, Monash University, Clayton, VIC, Australia.; Biomedicine Discovery Institute Cancer Program, Department of Physiology, Monash University, Clayton, VIC, Australia., Butler LM; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia., Tilley WD; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia.; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia., Conn SJ; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia., Lawrence MG; Biomedicine Discovery Institute Cancer Program, Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia.; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.; Cabrini Institute, Cabrini Health, Malvern, Melbourne, VIC, Australia.; Melbourne Urological Research Alliance (MURAL), Monash Biomedicine Discovery Institute Cancer Program, Monash University, Clayton, VIC, Australia., Wang S; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia., Selth LA; Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, Australia. luke.selth@flinders.edu.au.; Flinders University, Freemasons Centre for Male Health and Wellbeing, Bedford Park, SA, Australia. luke.selth@flinders.edu.au.; Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia. luke.selth@flinders.edu.au.
Jazyk:	angličtina
Zdroj:	British journal of cancer [Br J Cancer] 2024 Oct; Vol. 131 (6), pp. 1092-1105. Date of Electronic Publication: 2024 Aug 08.
DOI:	10.1038/s41416-024-02810-8
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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