title: Oncogenic MST1R activity in pancreatic and gastric cancer represents a valid target of HSP90 inhibitors.
abstract: OBJECTIVE
  To evaluate the effects of HSP90 blockade by EC154 on the oncogenic receptor tyrosine kinase macrophage-stimulating 1 receptor (MST1R) in gastric and pancreatic cancer.
  
  
  METHODS
  Impact of EC154 on signaling pathways was investigated by western blotting. Cancer cell migration was evaluated in Boyden chambers. Transcriptional regulation of MST1R was examined by using promoter-luciferase reporter constructs. Effects on MST1R expression, and tumor growth were investigated in in vivo tumor models.
  
  
  RESULTS
  MST1R was expressed by cancer cells without evidence of MST1R mutations. EC154 led to an effective inhibition of cancer cell growth, down-regulated MST1R, diminished its promoter activity, and disrupted oncogenic macrophage-stimulating protein 1 (MSP1) signaling. Moreover, pro-migratory activities of cancer cells were dramatically inhibited. In vivo, treatment with EC154 significantly reduced tumor growth, while MST1R expression was down-regulated.
  
  
  CONCLUSIONS
  Wild-type MST1R is an HSP90 client protein that can be targeted in gastrointestinal cancer using HSP90 inhibitors.
authors.affiliation: Department of Surgery, University of Regensburg Medical Center, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. christian.moser@ukr.de
authors.forename: Christian
authors.initials: C
authors.lastname: Moser
authors.forename: Sven A
authors.initials: SA
authors.lastname: Lang
authors.forename: Christina
authors.initials: C
authors.lastname: Hackl
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Victor
authors.initials: V
authors.lastname: Hong
authors.forename: Andres
authors.initials: A
authors.lastname: McKenzie
authors.forename: Bernhard
authors.initials: B
authors.lastname: Weber
authors.forename: Jung S
authors.initials: JS
authors.lastname: Park
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Young D
authors.initials: YD
authors.lastname: Jung
authors.forename: Oliver
authors.initials: O
authors.lastname: Stoeltzing
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases