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Updated: Jan 14, 2026
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic ductal adenocarcinoma
Maryam Safari1, Luigi Scotto2, Agnes Basseville3
1Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
Abstract:
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.
Insights
Combining histone deacetylase (HDAC) inhibitors with a novel RNA helicase inhibitor induces sustained hyperacetylation, synergistically reducing pancreatic cancer cell viability and tumor growth without toxicity. This epigenetic therapy offers a promising new treatment strategy.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with limited treatment options.
- Epigenetic therapies, particularly histone deacetylase (HDAC) inhibitors, show promise for targeting PDAC vulnerabilities.
- Resistance to HDAC inhibitors often arises due to reversible acetylation, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the synergistic effects of combining class I HDAC inhibitors with a novel RNA helicase eIF4A inhibitor, des-methyl pateamine A (DMPatA).
- To explore the underlying mechanisms of this combination therapy, focusing on histone acetylation, metabolic stress, and DNA damage.
- To evaluate the efficacy and toxicity of the combination therapy in preclinical models of PDAC.
Main Methods:
- In vitro studies using PDAC cell lines treated with HDAC inhibitors (e.g., romidepsin) and DMPatA.
- Assessment of cellular viability, histone acetylation levels, acetyl-CoA depletion, DNA damage, and gene expression.
- In vivo studies using mouse models of PDAC to evaluate tumor growth suppression and tissue-specific toxicity.
Main Results:
- The combination of HDAC inhibitors and DMPatA induced robust and persistent hyperacetylation, exceeding monotherapy effects.
- Synergistic reduction in PDAC cell viability was observed even at low, nontoxic drug doses.
- The combination triggered hypertranscription, metabolic stress, and augmented DNA damage, leading to effective tumor growth suppression in vivo without observable toxicity to normal tissues.
- No known resistance mechanisms like drug efflux were induced; elevated MYC expression sensitized cells to treatment.
Conclusions:
- Sustained hyperacetylation via combination therapy represents a novel strategy exploiting PDAC-specific vulnerabilities.
- This epigenetic approach simultaneously amplifies DNA damage and depletes essential acetyl-CoA, offering a potent anti-cancer effect.
- The synergistic combination demonstrates significant preclinical efficacy and supports translation to clinical settings for PDAC treatment.
