title: Src as a Therapeutic Target in Biliary Tract Cancer.
abstract: Src, a nonreceptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using 9 human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, and significantly increased G1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial-mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic antiproliferative and antimigratory effects. In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial-mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, because SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent antitumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising antitumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC. Mol Cancer Ther; 15(7); 1515-24. ©2016 AACR.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ah-Rong
authors.initials: AR
authors.lastname: Nam
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Bang
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Mei Hua
authors.initials: MH
authors.lastname: Jin
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea. ohdoyoun@snu.ac.kr.
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea. Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001661:Biliary Tract Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib; D019061:src-Family Kinases