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. 2014 Jun 19;33(25):3334-41.
doi: 10.1038/onc.2013.285. Epub 2013 Jul 22.

Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer

H-P Kim  1 , S-W Han  2 , S-H Song  1 , E-G Jeong  1 , M-Y Lee  3 , D Hwang  3 , S-A Im  2 , Y-J Bang  2 , T-Y Kim  4
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Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer

H-P Kim et al. Oncogene. .

Abstract

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.

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