ArticleCancer research and treatment2025
The Histone Deacetylase Inhibitor Entinostat Mediates HER2 Downregulation in Gastric Cancer, Providing the Basis for Its Particular Efficacy in HER2-Amplified Tumors and in Combination Therapies.
Article in Cancer research and treatment, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- The interplay of the microbiome, host genetics, and epigenetic modifications in gastric cancer.Frontiers in microbiology · 2026Review
- Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat.Neoplasia (New York, N.Y.) · 2025Article
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Authors and funding
9 authors.
Funding
Abstract
purposeHuman epidermal growth factor receptor 2 (HER2) inhibition represents a therapeutic approach with proven clinical efficacy in gastric cancer. However, resistance against HER2-directed therapeutics highlights the need for alternative approaches or drug combinations. Histone deacetylase inhibitors (HDACi) display a broad spectrum of antitumor properties, which may include effects on receptor tyrosine kinases. Materials and Methods: We analyzed the effects of the class I HDACi entinostat in a panel of HER2-amplified and non-amplified gastric adenocarcinoma cells in 2D cell culture as well as in tumor slice models ex vivo and in patient-derived xenografts in vivo. Effects on protein expression/signal transduction were evaluated by immunoblotting and quantitative reverse transcription polymerase chain reaction.
resultsHDAC inhibition reduced HER2 protein expression independently of initial HER2 expression levels. This was associated with the upregulation of the HER2-inhibiting microRNA miR-205. The downregulation of HER2 resulted in reduced AKT phosphorylation, apoptosis induction and antiproliferative effects, with particularly high efficiency in HER2-amplified gastric cancer cells. Inhibiting HER2 by a specific kinase inhibitor in gastric cancer cells with low basal HER2 expression led to HER2 upregulation. This was reversed by entinostat treatment and provided the basis for synergistic cell inhibition upon double treatment.
conclusionWe describe the downregulation of HER2 in gastric carcinoma cells upon HDACi treatment. Concomitantly, cells with high basal or treatment-induced HER2 expression showed most profound sensitivities towards HDACi. These findings may thus provide the basis for HDACi treatment as a therapeutic option particularly valuable in HER2-amplified gastric cancer and particularly useful in combination therapies with HER2 inhibitors.
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