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CDK9 inhibition constrains multiple oncogenic transcriptional and epigenetic pathways in prostate cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2024年8月8日

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  • Razia Rahman,
  • Muhammed H. Rahaman,
  • Adrienne R. Hanson,
  • Nicholas Choo,
  • Jianling Xie,
  • Scott L. Townley,
  • Raj 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

摘要

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.