title: Constitutively active FGFR3 with Lys650Glu mutation enhances bortezomib sensitivity in plasma cell malignancy.
abstract: The ectopically expressed fibroblast growth factor receptor 3 (FGFR3) and its constitutively active mutations have been detected in patients with multiple myeloma (MM). This study investigated whether the cytotoxic effects of bortezomib on malignant plasma cells are associated with FGFR3 expression and the existence of mutations of FGFR3.
  
  
  METHODS
  Cell apoptosis assays were performed in a plasmacytoma cell line, FR4 cells and a myeloma cell line, RPMI8226 cells overexpressing wild-type FGFR3 (FGFR3(WT)) or two different mutants, FGFR3(K650E) or FGFR3(Y373C), and the induction of endoplasmic reticulum (ER) stress protein was compared between each type of cell.
  
  
  RESULTS
  FR4 cells with FGFR3(K650E) showed enhanced sensitivity to bortezomib together with increased induction of ER stress proteins, compared to FR4 cells with mock, FGFR3(WT) or FGFR3(Y373C). RPMI8226 cells with FGFR3(K650E) also showed enhanced bortezomib sensitivity.
  
  
  CONCLUSIONS
  This study indicated that FGFR3K650E is associated with bortezomib sensitivity in malignant plasma cells via ER stress pathways.
authors.affiliation: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Otsuka
authors.forename: Masao
authors.initials: M
authors.lastname: Mizuki
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujita
authors.forename: Sumin
authors.initials: S
authors.lastname: Kang
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kanakura
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics*; D010950:Plasma Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D011719:Pyrazines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D012333:RNA, Messenger; D000069286:Bortezomib; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3