Mediator kinase inhibition reverses castration resistance of advanced prostate cancer

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.

Special Issue “Novel Chemical Tools for Targeted Cancer Therapy”

“…Indeed, selective inhibitors of the above-mentioned kinases prevented the survival of breast carcinoma cells treated with the estrogen signaling blocker fulvestrant [ 3 ]. Furthermore, the synergy with epidermal growth factor receptor antagonists, as well as circumvention of castration resistance in prostate cancer, demonstrated the efficacy of dual selective targeting of the tumor-specific mechanism and the transcription-regulating module which is generally tumor-independent but acts in concert with the antitumor drug [ 4 , 5 ]. In this scenario, the antitumor effect was achieved not via eschewing the principle of specific targeting but by ‘extending’ it to dual targeting, thereby keeping the validity of the concept.…”