Abstract A059: Epigenetic remodelling by class I HDAC inhibitors increases response to androgen signalling inhibitors in prostate cancer

Abstract

Abstract Prostate cancer (PCa) is one of the most prevalent cancers in the male population with approximately 1 in 8 men diagnosed with the disease during their lifetime. The treatment options available varies depending on individual circumstances, with surgery or radiotherapy employed as first-line treatments for locally advanced PCa whilst hormone therapies are employed as the disease progresses toward castrate-resistant prostate cancer. Despite the advances in therapies and initial treatment effectiveness, tumours develop resistance and overcoming this resistance proves a major challenge for the treatment of the disease. Dysregulation of chromatin regulatory proteins and the epigenetic landscape are key factors contributing to the development, progression and persistence of PCa. Histone deacetylases (HDACs) are a family of chromatin-modifying proteins which assemble into various transcriptional repressor complexes and mediate gene repression through the removal of acetyl groups from histone tails, subsequently compacting the chromatin landscape impacting on cell proliferation, transcription, replication and DNA repair. Overexpression of HDACs in prostate cancer has been shown to shift the balance of acetylation, resulting in improper gene silencing. Therefore, we hypothesise that restoration of the acetylation homeostasis through HDAC inhibition is a potential therapy to overcome resistance in PCa. Here, we show that the class I HDAC inhibitor Entinostat as a single agent promotes anti-tumour effects in PCa by impairing cell proliferation and inducing apoptosis in a panel of PCa cell lines. Interestingly, we found that combination with the androgen signalling inhibitors (ASIs), Enzalutamide or Abiraterone, further enhances these anti-tumour effects. In vitro analysis of matched parental and Enzalutamide-/Abiraterone-resistant C4-2B and CWRR-1 cells further revealed an enhanced reduction in cell survival following combined Entinostat and ASIs treatments in the resistant models compared to parental. Genomic and transcriptomic analyses uncovered distinct molecular signatures of these resistant models. Treatment with Entinostat alone downregulated androgen receptor (AR) expression and combination with ASI further suppressed AR expression and downstream AR target genes. Taken together, these results demonstrate the potential for Entinostat to synergise with current standard-of-care therapies to target ASI resistance in PCa. In conclusion, this study provides strong evidence suggesting the effectiveness of class I HDAC inhibition by Entinostat in the treatment of castration-resistant prostate cancer and opens the door for further research into combinatorial therapies in targeting resistance. Citation Format: Rachel McCole, Ben McCullough, Judith M. Manley, Nicholas Forsythe, Simon S. McDade, Melissa LaBonte Wilson. Epigenetic remodelling by class I HDAC inhibitors increases response to androgen signalling inhibitors in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A059.