title: MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate Cells.
abstract: Platelet-derived growth factor receptor beta (PDGFRβ) and hepatocyte growth factor receptor (MET) expressed on pancreatic stellate cells (PSCs) are suggested as important components modulating the interactions between pancreatic cancer cells (PCCs) and PSCs. The objective of this study is to clarify the effect of MK2461, a multikinase inhibitor targeting MET and PDGFRβ, on the interaction between PCCs and PSCs.
  
  
  
  In this study, we profiled the expression of receptor tyrosine kinases (including PDGFRβ and MET) in pancreatic cancer with quantitative targeted absolute proteomics using liquid chromatography tandem mass spectrometry. In addition, the effect of MK2461 on PCC-PSC interaction was investigated using PSCs prepared from pancreatic cancer tissues.
  
  
  
  In PSCs, PDGFRβ and MET were upregulated compared with other receptor tyrosine kinases. Conditioned medium from PSCs promoted the proliferation of PCCs, and vice versa. Moreover, MK2461 suppressed the effects of conditioned medium on PCCs and PSCs. Finally, MK2461 significantly inhibited tumor growth in mice coinjected with PCCs and PSCs.
  
  
  
  The PDGFRβ and MET may play a critical role in the interaction between PCCs and PSCs, which was modulated by MK2461. Therefore, MK2461 may have therapeutic potential in the treatment of pancreatic cancer.
authors.affiliation: From the *Department of Surgery, Tohoku University Graduate School of Medicine; and †Division of Membrane Transport and Drug Targeting, Department of Biochemical Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan.
authors.forename: Koetsu
authors.initials: K
authors.lastname: Inoue
authors.forename: Hideo
authors.initials: H
authors.lastname: Ohtsuka
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Motoi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shijo
authors.forename: Daisuke
authors.initials: D
authors.lastname: Douchi
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kawasaki
authors.forename: Kei
authors.initials: K
authors.lastname: Kawaguchi
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Masuda
authors.forename: Koji
authors.initials: K
authors.lastname: Fukase
authors.forename: Takeshi
authors.initials: T
authors.lastname: Naitoh
authors.forename: Yu
authors.initials: Y
authors.lastname: Katayose
authors.forename: Shinichi
authors.initials: S
authors.lastname: Egawa
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
mesh_terms: D000818:Animals; D001567:Benzocycloheptenes / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C561052:5H-benzo(4,5)cyclohepta(1,2-b)pyridin-5-one; D001567:Benzocycloheptenes; D011725:Pyridines; D019859:Proto-Oncogene Proteins c-met; D020797:Receptor, Platelet-Derived Growth Factor beta