Abstract 4235: PCNA and histone deacetylase targeted inhibitors in cutaneous T-cell lymphoma

Abstract AOH1996, a small molecule designed to bind proliferating cell nuclear antigen (PCNA), demonstrates selective inhibition of cancer cell growth across the NCI60 cell line panel with a mean GI50 of 300 nM, while exhibiting minimal toxicity to nonmalignant cells. Mechanistic studies reveal that AOH1996 influences DNA replication, cell cycle progression, DNA damage response, and transcription-replication conflicts. Inspired by phosphoproteomic analyses of AOH1996-treated cells, we investigated its potential in combination therapy with the histone deacetylase inhibitors (HDACi) vorinostat and belinostat. Notably, vorinostat, an FDA-approved treatment for cutaneous T-cell lymphoma (CTCL), exhibited synergistic effects with AOH1996 in cell viability assays with three CTCL derived cell lines. To better understand enhanced cell killing, we show combination drug effects on apoptosis, DNA damage and PCNA protein expression. Enhanced growth inhibition was also observed when AOH1996 was combined with other HDACi, such as domatinostat and panobinostat. These findings highlight the therapeutic potential of AOH1996 in combination with HDACi, particularly for CTCL, and pave the way for further exploration of this approach in cancer treatment. Citation Format: Caroline M. Li, Robert G. Lingeman, Long Gu, Robert J. Hickey, Linda H. Malkas. PCNA and histone deacetylase targeted inhibitors in cutaneous T-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4235.