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.
