Mediator kinase inhibition reverses castration resistance of advanced prostate cancer.

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 suppresses the growth of CRPC xenografts but also induces tumor regression and cures. Transcriptomic analysis revealed that Mediator kinase inhibition amplifies and modulates the effects of castration on gene expression, disrupting CRPC adaptation to androgen deprivation. Mediator kinase inactivation in tumor cells also affects stromal gene expression, indicating that Mediator kinase activity in CRPC molds the tumor microenvironment. The combination of castration and Mediator kinase inhibition downregulates the MYC pathway, and Mediator kinase inhibition suppresses a MYC-driven CRPC tumor model even without castration. CDK8/19 inhibitors show efficacy in patient-derived xenograft models of CRPC, and a gene signature of Mediator kinase activity correlates with tumor progression and overall survival in clinical samples of metastatic CRPC. These results indicate that Mediator kinases mediate androgen-independent in vivo growth of CRPC, supporting the development of CDK8/19 inhibitors for the treatment of this presently incurable disease.

The Journal of clinical investigation. 2024 Mar 28 [Epub ahead of print]

Jing Li, Thomas A Hilimire, Liu Yueying, Lili Wang, Jiaxin Liang, Balázs Győrffy, Vitali Sikirzhytski, Hao Ji, Li Zhang, Chen Cheng, Xiaokai Ding, Kendall R Kerr, Charles E Dowling, Alexander A Chumanevich, Zachary T Mack, Gary P Schools, Chang-Uk Lim, Leigh Ellis, Xiaolin Zi, Donald C Porter, Eugenia V Broude, Campbell McInnes, George Wilding, Michael B Lilly, Igor B Roninson, Mengqian Chen

Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, United States of America., Division of Hematology-Oncology, Medical University of South Carolina, Charlseton, United States of America., Department of Bioinformatics, Semmelweis University, Budapest, Hungary., Murtha Cancer Center Research Program, Department of Surgery, Center for Prostate Disease Research, Bethesda, United States of America., Chao Cancer Center, University of California, Irvine, irvine, United States of America., Senex Biotechnology, Inc., Columbia, United States of America.