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Mediator kinase inhibition reverses castration resistance of advanced prostate cancer. | LitMetric

AI Article Synopsis

  • CDK19 and CDK8 are important proteins that help control how genes work, and they are linked to a tough type of prostate cancer that doesn’t respond well to treatment after surgery or other therapies.
  • Blocking CDK19 and CDK8 can make this cancer respond better to treatment and even shrink tumors.
  • Using special treatments that target these proteins alongside other therapies can help control cancer growth and improve survival for patients with this difficult disease.

Article Abstract

Mediator kinases CDK19 and CDK8, pleiotropic regulators of transcriptional reprogramming, are differentially regulated by androgen signaling, but both kinases are upregulated in castration-resistant prostate cancer (CRPC). Genetic or pharmacological inhibition of CDK8 and CDK19 reverses the castration-resistant phenotype and restores the sensitivity of CRPC xenografts to androgen deprivation in vivo. Prolonged CDK8/19 inhibitor treatment combined with castration not only suppressed the growth of CRPC xenografts but also induced tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplified and modulated the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affected stromal gene expression, indicating that Mediator kinase activity in CRPC molded the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulated the MYC pathway, and Mediator kinase inhibition suppressed a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors showed efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlated with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediated androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093614PMC
http://dx.doi.org/10.1172/JCI176709DOI Listing

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