Oncogene, 2014-06, Vol.33 (25), p.3334-3341
2014
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- Autor(en) / Beteiligte
- Titel
- Testican-1-mediated epithelial–mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer
- Ist Teil von
- Oncogene, 2014-06, Vol.33 (25), p.3334-3341
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2014
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial–mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited β-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/onc.2013.285Titel-ID: cdi_proquest_miscellaneous_1554950452
- Format
- –
- Schlagworte
- AKT protein, Apoptosis, beta Catenin - genetics, beta Catenin - metabolism, Cancer, Cell Biology, Cell Cycle Checkpoints - drug effects, Cell Cycle Checkpoints - genetics, Cell Line, Tumor, Chemotherapy, Chronic exposure, Clinical trials, Drug resistance, Drug Resistance, Neoplasm, Epidermal growth factor, Epithelial-Mesenchymal Transition - drug effects, Epithelial-Mesenchymal Transition - genetics, ErbB-2 protein, Extracellular matrix, G1 Phase - drug effects, G1 Phase - genetics, Gastric cancer, Gefitinib, Gene expression, Genetic aspects, Genetic research, Growth factors, Human Genetics, Humans, Internal Medicine, Kinases, MAP kinase, Medicine, Medicine & Public Health, Mesenchyme, Oncology, Oncology, Experimental, original-article, Phenotypes, Properties, Protein kinase, Proteoglycans - genetics, Proteoglycans - metabolism, Proto-Oncogene Proteins c-met - genetics, Proto-Oncogene Proteins c-met - metabolism, Quinazolines - pharmacology, Receptor, ErbB-2 - genetics, Receptor, ErbB-2 - metabolism, Signal transduction, Signal Transduction - drug effects, Signal Transduction - genetics, siRNA, Stat3 protein, Stomach cancer, Stomach Neoplasms - drug therapy, Stomach Neoplasms - genetics, Stomach Neoplasms - metabolism, Transcription, Transcription, Genetic - drug effects, Trastuzumab, Tumor cell lines, Up-Regulation - drug effects, β-Catenin