Transcriptional Reprogramming in Prostate Cancer: Altered AR Activity, the Modulatory Role of CDK8/19, and Prospects for Combination Therapy

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with resistance to androgen-deprivation therapy (ADT) being the major clinical challenge. A key driver of this resistance is transcriptional reprogramming, during which androgen receptor (AR) activity shifts from ligand-dependent signaling to reactivation via splice variants such as AR-V7 and eventually to AR-negative states. The oncogene c-MYC plays a pivotal role through context-dependent crosstalk with AR, suppressing canonical AR-dependent transcription while promoting its own oncogenic program. This reprogramming is sustained by dysregulation of RB1/E2F, NF-κB, PI3K/AKT/mTOR, WNT/β-catenin, and Hippo/YAP/TAZ pathways, alongside N-MYC and L-MYC activation, forming an interconnected network driving phenotypic plasticity. This review focuses on cyclin-dependent kinases 8 and 19 (CDK8/19), components of the Mediator complex kinase module, as potential regulators of epigenetic plasticity in PCa capable of modulating both AR-dependent and AR-independent transcription. Preclinical studies show that CDK8/19 inhibition suppresses castration-resistant prostate cancer (CRPC) xenograft growth, restores ADT sensitivity, and additively enhances enzalutamide even in AR-V7-expressing resistant models, though the mechanisms of CDK8/19-mediated AR regulation remain largely undefined. We analyze the signaling pathways driving AR activity changes during PCa progression, evaluate potential mechanisms of CDK8/19-mediated AR regulation, and assess the therapeutic potential of CDK8/19 inhibitors with ADT.