Abstract A043: CDK8/19-regulated transcriptional reprogramming: a druggable driver of castration-resistant prostate cancer

Abstract

Abstract Androgen deprivation therapy (ADT) is the mainstay of prostate cancer (PCa) treatment. However, most patients with aggressive PCa become resistant to ADT and develop castration-resistant prostate cancer (CRPC). Newer androgen receptor (AR)-targeting CRPC treatments extend survival by only a few months, and metastatic CRPC (mCRPC) remains an incurable disease. Multiple mechanisms of ADT resistance have been identified, among which non-genetic (transcriptional) mechanisms are prominent, due to the high transcriptomic plasticity of PCa and the role of tumor microenvironment (TME) as a determinant of ADT resistance. PCa progression involves changes in the expression of CDK8 and CDK19, enzymatic components of the cyclin-dependent kinase module (CKM), associated with the transcriptional Mediator complex and implicated in transcriptional reprogramming and immune surveillance. We have investigated the roles of CDK8/19 Mediator kinases in CRPC, through bioinformatic analysis of primary PCa and mCRPC and by analyzing the effects of genetic and pharmacological inhibition of CDK8 and CDK19 on tumor growth and gene expression. CDK8 and CDK19 were found to be differentially regulated by androgen, which downregulates CDK8 and upregulates CDK19. Accordingly, CDK8 is decreased and CDK19 increased in primary PCa, where CDK19 is expressed higher than in any other tissues or tumors. However, both CDK19 and CDK8, as well as the other components of the CKM, are upregulated in mCRPC, concordantly with the changes in AR-mediated transcriptional signaling. Selective Mediator kinase inhibitors did not suppress PCa models driven by canonical AR signaling but inhibited in vivo growth of cell line-based and patient-derived xenograft (PDX) models of CRPC. Genetic inactivation of CDK8 and CDK19 suppressed 22Rv1 CRPC tumors in surgically or chemically castrated (but not intact) male NSG mice, whereas the expression of CDK19 or CDK8 reversed this phenotype. Transcriptomic analysis revealed that Mediator kinase inhibition exerted the strongest effects on gene expression in tumors growing in castrated mice, increasing the transcriptomic effects of castration on most of the genes regulated by CDK8/19, while decreasing its effects on some of the genes implicated in PCa progression. A gene signature reflecting Mediator kinase activity in CRPC xenografts correlated with shorter overall survival among mCRPC patients. Systemic treatment with a CDK8/19 inhibitor also affected stromal gene expression; many of these effects were reproduced by Mediator kinase mutagenesis in tumor cells alone, suggesting that Mediator kinases of tumor cells are involved in shaping the TME. Prolonged (up to 300 days) CDK8/19 inhibition induced not only growth inhibition but also shrinkage of CRPC tumors in nude mice (which contain NK cells that are stimulated by CDK8/19 inhibition) and even produced cures in 18-27% of animals. These results warrant the exploration of CDK8/19 Mediator kinase inhibitors for the treatment of the presently incurable CRPC. Citation Format: Jing Li, Thomas Hilimire, Yueying Liu, Lili Wang, Jiaxin Liang, Balazs Gyorffy, Vitali Sikitzhytski, Hao Ji, Li Zhang, Chen Cheng, Xiaokai Ding, Kendall Kerr, Charles Dowling, Gary Schools, Chang-Uk Lim, Eugenia Broude, George Wilding, Michael Lilly, Igor Roninson, Mengqian Chen. CDK8/19-regulated transcriptional reprogramming: a druggable driver of castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A043.