Mediator kinase inhibition reverses castration resistance of advanced prostate cancer
Jing Li, … , Igor B. Roninson, Mengqian Chen
Jing Li, … , Igor B. Roninson, Mengqian Chen
Published March 28, 2024
Citation Information: J Clin Invest. 2024;134(10):e176709. https://doi.org/10.1172/JCI176709.
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Research Article Oncology Therapeutics

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.

Authors

Jing Li, Thomas A. Hilimire, Yueying Liu, Lili Wang, Jiaxin Liang, Balazs Gyorffy, 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

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Figure 5

Transcriptomic effects of MKI on tumor (human) and stromal (mouse) genes in 22Rv1 xenografts.

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Transcriptomic effects of MKI on tumor (human) and stromal (mouse) genes...
(A) Number of tumor DEGs affected by MKI in Rv1-WT and Rv1-Luc (treated or untreated with SNX631) and in cells expressing wild-type (dKO-19) or kinase-deficient (dKO-19M) CDK19, in tumors growing in castrated (Cas) or intact (Int) male mice. (B) Effects of MKI and castration under the indicated conditions on the affected hallmark pathways in three 22Rv1 tumor models. (C) Heatmap of 315 tumor DEGs coregulated by MKI in three 22Rv1 models in the indicated comparisons. (D) Correlation between the effects of castration with and without MKI on the same DEGs in three 22Rv1 models. (E) Heatmaps of stromal DEGs affected in castrated animals by both SNX631 treatment and Mediator kinase mutagenesis (left) or by SNX631 treatment but not by Mediator kinase mutagenesis (right) under the indicated conditions.