Abstract 1850: From proteomic analysis to early investigations of combining inhibitors targeting PCNA and histone deacetylase

Abstract

Abstract Proteomic changes were investigated in a neuroblastoma cell line, SK-N-AS, treated with a small molecule inhibitor, AOH1996, designed to specifically bind proliferating cell nuclear antigen (PCNA) in cancer. PCNA is crucial to DNA replication, DNA repair, transcription, cell cycle control, and chromatin organization through interactions with different proteins. Pathway analysis of differential protein expressions between treated and untreated cells revealed less G2/M DNA damage checkpoint regulation and decreased assembly of RNA polymerase complex. Phosphoproteomic analysis by PTM Signature Enrichment Analysis (PTM-SEA) identified signatures of kinase activities, signaling pathways, and perturbations. Specifically, the histone deacetylase inhibitors belinostat and vorinostat were identified as enriched perturbation signatures. Both inhibitors were tested in combination with AOH1996 in SK-N-AS as well as cell lines derived from breast, lung, ovarian, and pancreatic cancer, revealing drug synergies at specific dose combinations. Western blot analysis showed that belinostat decreased protein expression of PCNA, suggestive of mechanistic synergies with AOH1996+belinostat combination therapies. Our proteomic analysis reveals a therapeutic potential of combining AOH1996 and histone deacetylase inhibitors for treating cancer with possibly lower drug dose and toxicities compared to single drug treatment. Citation Format: Caroline M. Li, Krystine Garcia-Mansfield, Robert G. Lingeman, Long Gu, Robert J. Hickey, Patrick Pirrotte, Linda H. Malkas. From proteomic analysis to early investigations of combining inhibitors targeting PCNA and histone deacetylase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1850.