ArticleGastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association2024
YAP inhibition overcomes adaptive resistance in HER2-positive gastric cancer treated with trastuzumab via the AKT/mTOR and ERK/mTOR axis.
Article in Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Integrating network pharmacology, molecular dynamics, and in vitro assays to unveil the mechanism of costunolide against gastric cancer.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- The impact of the PI3K/AKT/mTOR signaling pathway on trastuzumab resistance in HER2-positive gastric cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- The impact of the PI3K/AKT/mTOR signaling pathway on trastuzumab resistance in HER2-positive gastric cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- EVA1A-Mediated Signaling Networks in Physiological and Pathological Contexts: Dual Roles in Autophagy and Apoptosis.Cell biochemistry and biophysics · 2026Review
- Hippo-YAP/TAZ signaling in gastric cancer: molecular pathogenesis and emerging therapeutic horizons.Medical oncology (Northwood, London, England) · 2026Review
- Review
- Discussion on the mechanism of HER2 resistance in esophagogastric junction and gastric cancer in the era of immunotherapy.Human vaccines & immunotherapeutics · 2025Review
- The application of organoids in investigating immune evasion in the microenvironment of gastric cancer and screening novel drug candidates.Molecular cancer · 2025Review
- Predictive significance ofFrontiers in oncology · 2025Article
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10 authors.
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Abstract
backgroundHuman epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a heterogeneous GC subtype characterized by the overexpression of HER2. To date, few specific targeted therapies have demonstrated durable efficacy in HER2-positive GC patients, with resistance to trastuzumab typically emerging within 1 year. However, the mechanisms of resistance to trastuzumab remain incompletely understood, presenting a significant challenge to clinical practice.
methodsIn this study, we integrated genetic screening and bulk transcriptome and epigenomic profiling to define the mechanisms mediating adaptive resistance to HER2 inhibitors and identify potential effective therapeutic strategies for treating HER2-positive GCs.
resultsWe revealed a potential association between adaptive resistance to trastuzumab in HER2-positive GC and the expression of YES-associated protein (YAP). Notably, our investigation revealed that long-term administration of trastuzumab triggers extensive chromatin remodeling and initiates YAP gene transcription in HER2-positive cells characterized by the initial inhibition and subsequent reactivation. Furthermore, treatment of HER2-positive GC cells and cell line-derived xenografts (CDX) models with YAP inhibitors in combination with trastuzumab was found to induce synergistic effects through the AKT/mTOR and ERK/mTOR pathways.
conclusionThese findings underscore the pivotal role of reactivated YAP and mTOR signaling pathways in the development of adaptive resistance to trastuzumab and may serve as a promising joint target to overcome resistance to trastuzumab.
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