ArticleJournal of translational medicine2021
Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer.
Article in Journal of translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 37 citations in OpenAlex.
- Lenvatinib enhances the response of biliary tract cancer to anti-HER2 therapy.Signal transduction and targeted therapy · 2026Article
- Gastric Cancer Organoids: Mechanistic Insights, Drug Discovery, and Translational Advances in Precision Medicine.Journal of gastric cancer · 2026Review
- Article
- The evolving role of OMICS in gastrointestinal tumor biology and clinical practice.Molecular cancer · 2026Review
- Integrative In-silico, Network Pharmacology, Pharmacogenomics and In-vitro Evaluation of Fulvestrant-Loaded Zinc Oxide Nanoparticles Targeting HER2 Positive Breast Cancer.Pharmaceutical research · 2026Article
- Review
- Pathological characteristics and HER2 status of gastric cancer in Chinese high-incidence area.Medicine · 2026Article
- Kinase signaling cascades: an updated mechanistic landscape.Chemical science · 2025Review
- Lapatinib-Resistant HER2+ Breast Cancer Cells Are Associated with Dysregulation of MAPK and p70S6K/PDCD4 Pathways and Calcium Management, Influence of Cryptotanshinone.International journal of molecular sciences · 2025Article
- ERBB3-related gene PBX1 is associated with prognosis in patients with HER2-positive breast cancer.BMC genomic data · 2025Article
- Recent Advancements in Breast Cancer Therapies and Biomarkers: Mechanisms and Clinical Significance.Current pharmaceutical biotechnology · 2025Review
- Targeting PGK1 as a Novel strategy to regulate the sensitivity of HER2 positive gastric cancer to lapatinib.Frontiers in pharmacology · 2025Article
- Emerging role of MAPK signaling in glycosphingolipid-associated tumorigenesis.Glycoconjugate journal · 2024Review
- HER2-targeted therapies beyond breast cancer - an update.Nature reviews. Clinical oncology · 2024Review
- Review
- HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments.Cancers · 2024Review
- Targeting PI3K/AKT/mTOR and MAPK Signaling Pathways in Gastric Cancer.International journal of molecular sciences · 2024Review
- Identification of platelet-related subtypes and diagnostic markers in pediatric Crohn's disease based on WGCNA and machine learning.Frontiers in immunology · 2024Article
- Preclinical evaluation of the CDK4/6 inhibitor palbociclib in combination with a PI3K or MEK inhibitor in colorectal cancer.Cancer biology & therapy · 2023Article
- Characterization of Expression and Function of the Formins FHOD1, INF2, and DAAM1 in HER2-Positive Breast Cancer.Journal of breast cancer · 2023Article
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear.
methodsUsing mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies.
resultsPatients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM-1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05).
conclusionsPI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.
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