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

Oncogene volume 33, pages 3334–3341 (2014)Cite this article

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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Acknowledgements

This work was supported by grants from the Korean Healthcare 21 and Technology R&D Project; Ministry for Health, Welfare and Family Affairs (A091081) and in part by the Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2009-0093820).

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Authors and Affiliations

  1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

    H-P Kim, S-W Han, S-H Song, E-G Jeong, S-A Im, Y-J Bang & T-Y Kim

  2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

    S-W Han, S-A Im, Y-J Bang & T-Y Kim

  3. School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology(POSTECH), Pohang, Republic of Korea

    M-Y Lee & D Hwang

  4. WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea

    T-Y Kim

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Kim, HP., Han, SW., Song, SH. et al. Testican-1-mediated epithelial–mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer. Oncogene 33, 3334–3341 (2014). https://doi.org/10.1038/onc.2013.285

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