ArticleJournal of experimental & clinical cancer research : CR2022
HDAC class I inhibitor domatinostat sensitizes pancreatic cancer to chemotherapy by targeting cancer stem cell compartment via FOXM1 modulation.
Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 41 citations in OpenAlex.
- Mechanisms of Paclitaxel Resistance: Recent Advances and Future Perspectives.International journal of molecular sciences · 2026Review
- Liquid-liquid phase separation in cancer therapy resistance.iScience · 2026Review
- USP25 attenuates the immunosuppressive tumor microenvironment via the deubiquitination of TAB2 in head and neck squamous cell carcinoma.Cell death discovery · 2025Article
- Epigenetic reprogramming as the nexus of cancer stemness and therapy resistance: implications for biomarker discovery.Discover oncology · 2025Review
- Valproic acid improves the efficacy of oxaliplatin/fluoropyrimidine-based chemotherapy by targeting cancer stem cell via β-Catenin modulation in colorectal cancer.Cell death & disease · 2025Article
- Targeting epigenetic regulators as a promising avenue to overcome cancer therapy resistance.Signal transduction and targeted therapy · 2025Review
- DLK1 Distinguishes Subsets of NF1-Associated Malignant Peripheral Nerve Sheath Tumors with Divergent Molecular Signatures.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma.Journal of experimental & clinical cancer research : CR · 2025Article
- Clinical application and drug resistance mechanism of gemcitabine.Frontiers in cell and developmental biology · 2025Review
- FOXM1-Driven CKS1B Upregulation Promotes Pancreatic Cancer Progression and Therapeutic Resistance.International journal of biological sciences · 2025Article
- Copper-Based Metal-Organic Framework Nanoplatform for miRNA Delivery: Synergistic Antitumor Therapy.International journal of nanomedicine · 2025Article
- Epigenetic modification of hepatitis B virus infection and related hepatocellular carcinoma.Virulence · 2024Review
- Interplay between epigenetics, senescence and cellular redox metabolism in cancer and its therapeutic implications.Redox biology · 2024Review
- Article
- Identification of TEFM as a potential therapeutic target for LUAD treatment.Journal of translational medicine · 2024Article
- Novel Histone Deacetylase (HDAC) Inhibitor Induces Apoptosis and Suppresses Invasion via E-Cadherin Upregulation in Pancreatic Ductal Adenocarcinoma (PDAC).Pharmaceuticals (Basel, Switzerland) · 2024Article
- Transcriptional regulation of cancer stem cell: regulatory factors elucidation and cancer treatment strategies.Journal of experimental & clinical cancer research : CR · 2024Review
- Altered histone acetylation patterns in pancreatic cancer cell lines induce subtype‑specific transcriptomic and phenotypical changes.International journal of oncology · 2024Article
- Deacetylation of Histones and Non-histone Proteins in Inflammatory Diseases and Cancer Therapeutic Potential of Histone Deacetylase Inhibitors.Current genomics · 2023Review
- FOXM1: A small fox that makes more tracks for cancer progression and metastasis.Seminars in cancer biology · 2023Review
Corrections and comments
- Erratum issued
Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundPancreatic ductal adenocarcinoma (PDAC) represents an unmet clinical need due to the very poor prognosis and the lack of effective therapy. Here we investigated the potential of domatinostat (4SC-202), a new class I histone deacetylase (HDAC) inhibitor, currently in clinical development, to sensitize PDAC to first line standard gemcitabine (G)/taxol (T) doublet chemotherapy treatment.
methodsSynergistic anti-tumor effect of the combined treatment was assessed in PANC1, ASPC1 and PANC28 PDAC cell lines in vitro as well as on tumor spheroids and microtissues, by evaluating combination index (CI), apoptosis, clonogenic capability. The data were confirmed in vivo xenograft models of PANC28 and PANC1 cells in athymic mice. Cancer stem cells (CSC) targeting was studied by mRNA and protein expression of CSC markers, by limiting dilution assay, and by flow cytometric and immunofluorescent evaluation of CSC mitochondrial and cellular oxidative stress. Mechanistic role of forkhead box M1 (FOXM1) and downstream targets was evaluated in FOXM1-overexpressing PDAC cells.
resultsWe showed that domatinostat sensitized in vitro and in vivo models of PDAC to chemotherapeutics commonly used in PDAC patients management and particularly to GT doublet, by targeting CSC compartment through the induction of mitochondrial and cellular oxidative stress. Mechanistically, we showed that domatinostat hampers the expression and function of FOXM1, a transcription factor playing a crucial role in stemness, oxidative stress modulation and DNA repair. Domatinostat reduced FOXM1 protein levels by downregulating mRNA expression and inducing proteasome-mediated protein degradation thus preventing nuclear translocation correlated with a reduction of FOXM1 target genes. Furthermore, by overexpressing FOXM1 in PDAC cells we significantly reduced domatinostat-inducing oxidative mitochondrial and cellular stress and abolished GT sensitization, both in adherent and spheroid cells, confirming FOXM1 crucial role in the mechanisms described. Finally, we found a correlation of FOXM1 expression with poor progression free survival in PDAC chemotherapy-treated patients.
conclusionsOverall, we suggest a novel therapeutic strategy based on domatinostat to improve efficacy and to overcome resistance of commonly used chemotherapeutics in PDAC that warrant further clinical evaluation.
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