Abstract 2357: Inhibition of CDK8/19 mediator kinase suppresses primary and metastatic growth of castration-resistant prostate cancer

Abstract

Abstract Following androgen deprivation therapy (ADT), prostate cancers (PCa) progress to castration resistant prostate cancer (CRPC) status, independent of androgen signaling, through changes in androgen receptor (AR) or by converting to AR-negative forms. Metastatic CRPC remains incurable, and the most potent new drugs prolong survival by only a few months. There is an urgent need for novel agents against advanced CRPC. CDK8 and CDK19 are two isoforms of Mediator kinase, which regulates transcriptional reprogramming, a key process in cancer development, metastasis, and drug resistance. Bioinformatic analysis of clinical prostate cancers shows that CDK19 expression increases during PCa development and progression reaching higher levels than in any other cancers, whereas CDK8 expression increases when PCa becomes CRPC. We have investigated the effects of CDK8/19 Mediator kinase inhibition on gene expression and tumor growth in several CPRC tumor models, growing subcutaneously or in the bone, the principal cause of PCa lethality. CDK8/19 inhibition decreased androgen-stimulated expression of the most strongly androgen-regulated genes, including PSA, in androgen-responsive PCa in vitro and in vivo. CRISPR knockout of both CDK8 and CDK19 in 22Rv1 CRPC cells that express both full-length AR and its androgen-independent V7 variant, had little effect on the tumor growth in intact male mice but strongly suppressed tumor growth in castrated animals. Moreover, re-expression of CDK19 but not of its kinase-dead mutant partially restored tumor growth in castrated mice. Similarly, SNX631, a selective CDK8/19 inhibitor, had little effect on 22Rv1 growth in intact mice but strongly suppressed the growth of these cells (but not of their knockout derivative) in castrated mice. Prolonged (up to 300 days) treatment with SNX631 induced tumor shrinkage and disappearance in a subset of 22Rv1 tumors grown in castrated animals. Transcriptomic analysis revealed that CDK8/19 inhibition or knockout suppressed castration-induced transcriptional reprogramming in tumor cells and affected stromal gene expression. SNX631 also inhibited the growth of a CRPC PDX derived from a PCa patient who failed casodex, abiraterone, and docetaxel, in castrated mice. SNX631 also significantly inhibited in vivo growth of AR-negative PC3 cells both in the flank and in the bone, the principal metastatic site of PCa. These results warrant the development of CDK8/19 inhibitors for the presently incurable metastatic CRPC. Funding acknowledgement: This research was funded by NIH grant R44CA203184 (M.C., I.R., M.L., Y.S.) Citation Format: Jing Li, Thomas Hilimire, Chen Cheng, Eugenia V. Broude, Yueying Liu, Michael B. Lilly, Yusuke Shiozawa, George Wilding, Igor B. Roninson, Mengqian Chen. Inhibition of CDK8/19 mediator kinase suppresses primary and metastatic growth of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2357.