BMB Reports 2018; 51(12): 660-665  https://doi.org/10.5483/BMBRep.2018.51.12.259
HSP90 inhibitor, AUY922, debilitates intrinsic and acquired lapatinib-resistant HER2-positive gastric cancer cells
Kang-Seo Park1,2, Yong Sang Hong1, Junyoung Choi1, Shinkyo Yoon1, Jihoon Kang1,3, Deokhoon Kim4, Kang-Pa Lee2, Hyeon-Su Im5, Chang Hoon Lee6, Seyoung Seo1, Sang-We Kim1, Dae Ho Lee1,* and Sook Ryun Park1,*
1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, 2Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 05505, 3Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181 , 4Asan Institute for Life Science, Department of Pathology, Asan Medical Center, Seoul 05505, 5Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, 6Bio & Drug Discovery Division, Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea
Correspondence to: *Corresponding authors. Dae Ho Lee, Tel: +82-2-3010-3214; Fax:+82-2-3010-6961; E-mail: leedaeho@amc.seoul.kr; Sook Ryun Park, Tel: +82-2-3010-3206; Fax: +82-2-3010-6954; E-mail: srpark@amc.seoul.kr
Received: November 9, 2018; Revised: November 15, 2018; Accepted: November 28, 2018; Published online: December 31, 2018.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

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Abstract
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.
Keywords: AUY922, Drug resistance, Gastric cancer, HER2, Lapatinib


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