title: Targeting c-MET by LY2801653 for treatment of cholangiocarcinoma.
abstract: Palliative treatment options for human cholangiocarcinoma (CCC) are quite limited and new therapeutic strategies are of utmost need. c-MET has been shown to be deregulated in many cancers, but the role of c-MET in the carcinogenesis of CCC remains unclear. The main purpose of this study is to evaluate the expression and also to investigate the role of c-MET and its effective inhibition for the treatment of CCC. In this study we investigated the effects of LY2801653, a small-molecule inhibitor with potent activity against MET kinase, in human CCC cell lines and in vivo using a xenograft mouse model. We have investigated the role of c-MET and its inhibitory effects on migration, invasion, colony formation, MET downstream targets, and CCC tumor growth. We also analyzed the role of apoptosis and senescence as well as the influence of hypoxia in this context. c-MET and p-MET were expressed in 72% and 12.5% of human CCC tissues and in TFK-1, SZ-1 cell lines. MET inhibition was achieved by blocking phosphorylation of MET with LY2801653 and subsequent down regulation of c-MET downstream targets. Treatment showed in a xenograft model potent anti-tumor activity. LY2801653 is an effective inhibitor and suppress the proliferation of CCC cells as well as the growth of xenograft tumors. Therefore, inhibition of c-MET could be a possible alternative approach for the treatment of human CCC. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, Tübingen, Germany.
authors.forename: Samarpita
authors.initials: S
authors.lastname: Barat
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, Tübingen, Germany.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bozko
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, Tübingen, Germany.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, Tübingen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Scholta
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, Tübingen, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Hanert
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, Tübingen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Götze
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, Tübingen, Germany.
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.affiliation: Institute of Pathology, Nordstadt Krankenhaus, Haltenhoffstr. 41, Hannover, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wilkens
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Otfried-Mueller-Str. 10, Tübingen, Germany.
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Plentz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001652:Bile Ducts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C586252:merestinib; D019859:Proto-Oncogene Proteins c-met
keywords: LY2801653; c-MET; cholangiocarcinoma; p-MET; small-molecule inhibitor