Abstract A044: Strategic chromatin remodelling by class I HDAC inhibition restores apoptotic competence in androgen-sensitive and resistant prostate cancer

Abstract Background Resistance to androgen-receptor signalling inhibitors (ARSIs) remain a major clinical obstacle in advanced prostate cancer (PCa), frequently arising through epigenetic plasticity that sustains tumour survival despite AR blockade. Class I histone deacetylases (HDACs) are overexpressed in PCa, driving chromatin compaction and aberrant transcriptional programmes. We hypothesised that inhibition of class I HDACs with Entinostat restores acetylation homeostasis and transcriptional accessibility, thereby reengaging apoptotic pathways and re-sensitising tumours to AR-targeted therapy. Methods Matched parental and enzalutamide-resistant (EnzR) PCa models were treated with Entinostat ± Enzalutamide. Effects on proliferation and survival were assessed by SRB and clonogenic assays; apoptosis by caspase-3/7 activity and PARP cleavage. Transcriptional and chromatin changes were profiled by RNA-seq and immunoblotting. Functional dependences were tested using BIM/PUMA knock-down. In vivo efficacy was assessed in CWR-R1 xenografts. Results Entinostat significantly reduced proliferation, induced apoptosis, and suppressed AR expression and downstream targets, accompanied by global increases in histone H3 acetylation and transcriptional reprogramming. Combined Entinostat + Enzalutamide treatment produced additive suppression of AR signalling and enhanced apoptotic activity. Mechanistically, Entinostat activated a FOXO-mediated apoptotic axis, upregulating BIM (BCL2L11) and PUMA (BBC3) while simultaneously downregulating the anti-apoptotic mediator FLIP, thereby engaging both intrinsic and extrinsic cell-death pathways. Loss of BIM and/or PUMA partially rescued Entinostat-induced death, confirming their functional requirement. In vivo, Entinostat significantly reduced tumour growth with minimal adverse effects. Conclusions Class I HDAC inhibition remodels the chromatin landscape and restores apoptotic competence in Enzalutamide-resistant PCa through coordinated activation of FOXO-driven death signalling and repression of AR-dependent transcription. These findings provide a strong preclinical rationale for clinical evaluation of Entinostat as both monotherapy and in combination with AR blockade in castration-resistant PCa (CRPC), and highlight apoptotic and chromatin-accessibility signatures as potential biomarkers of response. Citation Format: Rachel McCole, Judith Manley, Deborah Y. Moss, Ben McCullough, Cheryl Latimer, Letitia Mohamed-Smith, Nicholas Forsthye, Lucy Wilson, Shauna McClelland, Fatemeh Mirzadehazad, Keelan Farnan, Tríona Ní Chonghaile, Gemma Gregg, Yaser Atlasi, Suneil Jain, David J. J. Waugh, Simon S. McDade, Melissa J. LaBonte Wilson. Strategic chromatin remodelling by class I HDAC inhibition restores apoptotic competence in androgen-sensitive and resistant prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr A044.