PROSTATE cancer remains the most commonly diagnosed cancer in men, with over 1.4 million new cases globally each year. While treatments like prostatectomy and radiotherapy are effective for many patients with high-risk localised disease, around 25% eventually develop metastases. At this advanced stage, androgen deprivation therapy (ADT) is the standard treatment, but progression to metastatic castration-resistant prostate cancer (mCRPC) is inevitable.
Enzalutamide (ENZA), an androgen receptor (AR) inhibitor, is a key therapy for mCRPC, yet resistance, often present from the outset, affects nearly half of all patients. To understand the basis of this resistance, researchers examined epigenetic factors, particularly changes in chromatin accessibility marked by H3K27ac, a signal of active gene expression. Biopsies from patients before and after AR-targeted treatments revealed 657 H3K27ac sites enriched in tumours from non-responders. These epigenetic signatures were linked to genes upregulated in resistant cancer cells, offering potential biomarkers for poor ENZA response.
Further analysis identified HDAC3 and the glucocorticoid receptor (GR) as key players in drug resistance. The study found that vorinostat, a pan-HDAC inhibitor, reduced tumour growth in models of ENZA-resistant disease, and suppressed GR binding at resistance-associated chromatin sites. Although side effects such as diarrhoea were noted in vivo, the findings suggest that HDAC3 inhibition may counteract resistance mechanisms when combined with ENZA.
The research also highlights the role of non-coding genomic elements in disease progression and therapy failure. Enhancer alterations, epigenetic plasticity, and transcription factor reprogramming all contribute to mCRPC’s complexity. By identifying specific epigenetic markers and drug targets, this study paves the way for future trials exploring HDAC inhibitors like vorinostat as part of combination therapies.
Ultimately, these insights support the use of epigenetic profiling to personalise treatment and improve outcomes for patients with mCRPC, a condition for which curative therapies remain urgently needed.
Reference
Severson TM et al. Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer. Cell Rep Med. 2025;6(7):102215.
