ArticleMolecular cancer therapeutics2012
MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells.
Article in Molecular cancer therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 109 papers.
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The trial behind it
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Who cites it
109 citing papers in PubMed, 176 citations in OpenAlex.
- Biomarker analysis of the GATSBY study of trastuzumab emtansine versus a taxane in previously treated HER2-positive advanced gastric/gastroesophageal junction cancer.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2019Trial
- Trial
- A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.Breast cancer research : BCR · 2017Trial
- Molecular effects of Lapatinib in the treatment of HER2 overexpressing oesophago-gastric adenocarcinoma.British journal of cancer · 2015Trial
- Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma.The Journal of clinical investigation · 2014Trial
- Review
- Acquired resistance of cancer therapies: Mechanisms and perspectives.Chinese medical journal · 2026Review
- Construction of a survival prognosis model for epithelial-mesenchymal transition-related genes in gastric cancer.European journal of medical research · 2025Article
- Targeting mesenchymal-epithelial transition factor signaling in cancer: from genetic alterations to clinical advances and future prospects.Molecular biology reports · 2025Review
- Evolving roles of MET as a therapeutic target in NSCLC and beyond.Nature reviews. Clinical oncology · 2025Review
- A molecular switch from tumor suppressor to oncogene in ER+ve breast cancer: Role of androgen receptor, JAK-STAT, and lineage plasticity.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- HER2-targeted therapies beyond breast cancer - an update.Nature reviews. Clinical oncology · 2024Review
- Advances in Personalized Oncology.Cancers · 2024Review
- Review
- Research progress on the development of hepatocyte growth factor/c-Met signaling pathway in gastric cancer: A review.World journal of gastrointestinal oncology · 2024Review
- Activity-based protein profiling and global proteome analysis reveal MASTL as a potential therapeutic target in gastric cancer.Cell communication and signaling : CCS · 2024Article
- Ferroptosis regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer.World journal of gastrointestinal oncology · 2024Article
- Characterization of MET Alterations in 37 Gastroesophageal Cancer Cell Lines for MET-Targeted Therapy.International journal of molecular sciences · 2024Article
- HER2International journal of oncology · 2024Review
- Clinical Implication of Concurrent Amplification of MET and FGFR2 in Metastatic Gastric Cancer.Biomedicines · 2023Article
49 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
HER2 amplification is found in more than 15% of gastric cancers and is associated with poor clinical outcome. Lapatinib, a dual HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown promising in vitro results in treating HER2(+) cancer cells. However, several studies have shown that activation of alternative receptor tyrosine kinases can mediate resistance to HER-targeted therapy. Here, we investigated whether activated MET can confer resistance to lapatinib inhibition of gastric cancer cells. A panel of gastric cancer cell lines was treated with lapatinib, and we observed that cell proliferation was reduced by 70% and that the degree of HER2 amplification corresponds to sensitivity to lapatinib. Immunoblotting analysis indicated that phosphorylation of HER2, EGFR, MET, AKT, and extracellular signal-regulated kinase was inhibited by lapatinib and presumably led to cell-cycle arrest as observed with flow cytometry. Hepatocyte growth factor (HGF) activation of MET receptors rescued cells from lapatinib-induced growth inhibition by restimulating the downstream pathways and restoring normal cell-cycle progression. This rescue effect could be abrogated by inhibiting MET with PHA-665752 (a highly specific MET inhibitor) or downregulating MET expression with short interfering RNA. No synergy in growth inhibition was observed when cells were treated with a combination of lapatinib and PHA-665752. Repeat studies using insulin-like growth factor 1 and fibroblast growth factor 3 could not uniformly rescue the lapatinib-treated gastric cancer cells. In conclusion, HGF/MET-mediated resistance to lapatinib is a novel mechanism of resistance to HER2-targeted agents in gastric cancer cells. Development of inhibitors targeting multiple receptors or common downstream signaling proteins merits further investigation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.