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생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
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HSP90 inhibitor, AUY922, debilitates intrinsic and acquired lapatinib-resistant HER2-positive gastric cancer cells

  • Park, Kang-Seo (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Hong, Yong Sang (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Junyoung (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yoon, Shinkyo (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kang, Jihoon (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Deokhoon (Asan Institute for Life Science, Department of Pathology, Asan Medical Center) ;
  • Lee, Kang-Pa (Department of Biomedical Sciences, University of Ulsan College of Medicine) ;
  • Im, Hyeon-Su (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Chang Hoon (Bio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology (KRICT)) ;
  • Seo, Seyoung (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Sang-We (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Dae Ho (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Park, Sook Ryun (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
  • 투고 : 2018.11.09
  • 심사 : 2018.11.28
  • 발행 : 2018.12.31
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초록

Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib.

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참고문헌

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