Abstract 7319: Targeting HDAC1 activity presents vulnerabilities in pancreatic cancer metabolism

Abstract Pancreatic cancer is a lethal disease with significant metabolic reprogramming, which promotes tumor growth, therapy resistance, and adaptation to stress. These alterations are largely attributed to mutations in the KRAS oncogene but with limited progress in therapeutic discovery. Despite the recent focus on metabolism in pancreatic cancer, the major mediators of altered metabolism remain unknown. Our differential gene expression analyses in multiple patient cohorts’ pancreatic tumors versus normal tissues identify histone deacetylase 1 (HDAC1) as a consistently upregulated epigenetic gene. HDAC1-high tumors correlate strongly with metabolic pathways, including glycolysis, redox metabolism, and nucleotide biosynthesis. Using CRISPR/Cas9 gene editing, we found that the deletion of HDAC1 in pancreatic cancer cell lines triggers metabolic shifts, notably in glucose metabolism, and led to a distinct growth phenotype in a cell context-dependent manner. Similarly, treatment with class I selective HDAC inhibitors was selectively effective in suppressing pancreatic cancer cell growth. Furthermore, our drug screenings demonstrate profound synergies that overlap across the HDAC1-deleted and HDACi treated cell lines that present under-explored avenues for therapeutics. Our data provides evidence of compensatory metabolic alterations upon HDAC1 inhibition, which could broaden the opportunities for therapeutic intervention in pancreatic cancer. Citation Format: Don-Gerard C. Conde, Evan J. Zhou, Soren Jensen, Maximillian Farma, Chiamaka Joy Ezeh, Alexander N. Behram, Phuong T. Pham, Nabila N. Binti, Laiba Shiekh, Matthew C. Cheung, Zeribe Nwosu, . Targeting HDAC1 activity presents vulnerabilities in pancreatic cancer metabolism abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7319.