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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics*
  • G1 Phase / drug effects
  • G1 Phase / genetics
  • Humans
  • Lapatinib
  • 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 / drug effects
  • Signal Transduction / genetics*
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Proteoglycans
  • Quinazolines
  • SPOCK1 protein, human
  • beta Catenin
  • Lapatinib
  • ERBB2 protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor, ErbB-2