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Testican-1-mediated epithelial–mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer
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Testican-1-mediated epithelial–mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer
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Journal Article
Testican-1-mediated epithelial–mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer
2014
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Cancer
/ Cell Cycle Checkpoints - drug effects
/ Cell Cycle Checkpoints - genetics
/ Epithelial-Mesenchymal Transition - drug effects
/ Epithelial-Mesenchymal Transition - genetics
/ Humans
/ Kinases
/ Medicine
/ Oncology
/ Proto-Oncogene Proteins c-met - genetics
/ Proto-Oncogene Proteins c-met - metabolism
/ Receptor, ErbB-2 - metabolism
/ Signal Transduction - drug effects
/ Signal Transduction - genetics
/ siRNA
/ Stomach Neoplasms - drug therapy
/ Stomach Neoplasms - genetics
/ Stomach Neoplasms - metabolism
/ Transcription, Genetic - drug effects
