Related Experiment Video

Updated: Jun 29, 2025

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

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Mediator kinase inhibition reverses castration resistance of advanced prostate cancer

Jing Li1, Thomas A Hilimire1,2, Yueying Liu3

  • 1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA.

The Journal of Clinical Investigation
|March 28, 2024
PubMed

Insights

Inhibition of Mediator kinases CDK8 and CDK19 reverses castration-resistant prostate cancer (CRPC) progression. Combination therapy with castration induced tumor regression and cures in CRPC models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mediator kinases CDK8 and CDK19 regulate gene transcription and are implicated in cancer.
  • These kinases are upregulated in castration-resistant prostate cancer (CRPC), a form of advanced prostate cancer.
  • Androgen signaling differentially regulates CDK8 and CDK19, but both are elevated in CRPC.

Purpose of the Study:

  • To investigate the role of Mediator kinases CDK8 and CDK19 in CRPC progression.
  • To evaluate the therapeutic potential of inhibiting CDK8 and CDK19 in CRPC models.

Main Methods:

  • Genetic and pharmacological inhibition of CDK8 and CDK19 in CRPC xenografts.
  • Transcriptomic analysis to assess gene expression changes.
  • Evaluation of combination therapy with castration.
  • Assessment in patient-derived xenograft models and clinical samples.

Main Results:

  • CDK8/19 inhibition reversed the castration-resistant phenotype and restored sensitivity to androgen deprivation.
  • Combined inhibition with castration led to tumor regression and cures in vivo.
  • Mediator kinase inhibition modulated castration's effects on gene expression and the tumor microenvironment.
  • Downregulation of the MYC pathway was observed, and CDK8/19 inhibition suppressed MYC-driven CRPC models.
  • Efficacy was confirmed in patient-derived xenografts, and a Mediator kinase activity gene signature correlated with CRPC progression and survival.

Conclusions:

  • Mediator kinases CDK8 and CDK19 drive androgen-independent growth in CRPC.
  • Targeting CDK8/19 represents a promising therapeutic strategy for CRPC.
  • Combination therapy of CDK8/19 inhibitors with castration shows significant potential for treating advanced prostate cancer.
Keywords:
OncologyTherapeuticsTranscription

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