title: Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer.
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.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: H-P
authors.initials: HP
authors.lastname: Kim
authors.affiliation: 1] Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: S-W
authors.initials: SW
authors.lastname: Han
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Song
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: E-G
authors.initials: EG
authors.lastname: Jeong
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology(POSTECH), Pohang, Republic of Korea.
authors.forename: M-Y
authors.initials: MY
authors.lastname: Lee
authors.affiliation: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology(POSTECH), Pohang, Republic of Korea.
authors.forename: D
authors.initials: D
authors.lastname: Hwang
authors.affiliation: 1] Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: S-A
authors.initials: SA
authors.lastname: Im
authors.affiliation: 1] Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Bang
authors.affiliation: 1] Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea [2] Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea [3] WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Kim
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000077341:Lapatinib; D011509:Proteoglycans / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000077341:Lapatinib; D011509:Proteoglycans; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D051176:beta Catenin; C504369:SPOCK1 protein, human; C508053:ERBB2 protein, human