Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Emerging evidence suggests that epigenetic therapies have the potential to target key mechanisms driving PDAC progression and therapy resistance. Previous efforts to target KRAS-driven metabolic vulnerabilities, including dependence on enhanced fatty acid synthesis, have highlighted the potential for histone deacetylase (HDAC) inhibitors to deplete acetyl-CoA and induce DNA damage through histone acetylation, while resistance emerges at least in part due to the reversible nature of HDAC inhibitor-induced acetylation. In this work, we discovered that the combination of class I histone deacetylase (HDAC) inhibitors, such as romidepsin, with a novel RNA helicase eIF4A inhibitor, des-methyl pateamine A (DMPatA), induces robust and persistent hyperacetylation, significantly exceeding the levels and duration observed with HDAC inhibitor monotherapy. This combination synergistically reduces the viability of PDAC cells, even at low, nontoxic doses for both drugs. This unexpected synergistic effect triggers a cascade of cellular responses, including hypertranscription, metabolic stress, and augmented DNA damage. Sustained hyperacetylation represents a novel mechanism exploiting PDAC-specific vulnerabilities, simultaneously amplifying DNA damage and depleting acetyl-CoA levels critical for their aberrant proliferation. In vivo, the combination effectively suppresses tumor growth, showing no toxicity to normal tissues but sustained hyperacetylation in tumor tissue. The combination does not appear to induce known resistance mechanisms such as drug efflux; elevated MYC expression, rather than inducing resistance, sensitizes PDAC cells to treatment. These studies support translation of this synergistic combination to the clinic.
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