title: Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models.
abstract: BACKGROUND
  Fibroblast growth factor receptor (FGFR) signalling has been implicated in pancreas carcinogenesis. We investigated the effect of FGFR inhibition in pancreatic cancer in complementary cancer models derived from cell lines and patient-derived primary tumour explants.
  
  
  METHODS
  The effects of FGFR signalling inhibition in pancreatic cancer were evaluated using anti-FRS2 shRNA and dovitinib. Pancreatic cancers with varying sensitivity to dovitinib were evaluated to determine potential predictive biomarkers of efficacy. Primary pancreatic explants with opposite extreme of biomarker expression were selected from 13 tumours for in vivo dovitinib treatment.
  
  
  RESULTS
  Treatment with anti-FRS2 shRNA induced significant in vitro cell kill in pancreatic cancer cells. Dovitinib treatment achieved similar effects and was mediated by Akt/Mcl-1 signalling in sensitive cells. Dovitinib efficacy correlated with FRS2 phosphorylation status, FGFR2 mRNA level and FGFR2 IIIb expression but not phosphorylation status of VEGFR2 and PDGFRβ. Using FGFR2 mRNA level, a proof-of-concept study using primary pancreatic cancer explants correctly identified the tumours' sensitivity to dovitinib.
  
  
  CONCLUSIONS
  Inhibiting FGFR signalling using shRNA and dovitinib achieved significant anti-cancer cancer effects in pancreatic cancer. The effect was more pronounced in FGFR2 IIIb overexpressing pancreatic cancer that may be dependent on aberrant stimulation by stromal-derived FGF ligands.
authors: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton streets, Buffalo, NY 14263, USA.
authors: H
authors: H
authors: Zhang
authors: Department of Immunity, Roswell Park Cancer Institute, Elm & Carlton streets, Buffalo, NY 14263, USA.
authors: B L
authors: BL
authors: Hylander
authors: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton streets, Buffalo, NY 14263, USA.
authors: C
authors: C
authors: LeVea
authors: Department of Immunity, Roswell Park Cancer Institute, Elm & Carlton streets, Buffalo, NY 14263, USA.
authors: E A
authors: EA
authors: Repasky
authors: Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
authors: R M
authors: RM
authors: Straubinger
authors: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton streets, Buffalo, NY 14263, USA.
authors: A A
authors: AA
authors: Adjei
authors: Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton streets, Buffalo, NY 14263, USA.
authors: W W
authors: WW
authors: Ma
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D048868:Adaptor Proteins, Signal Transducing; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; C106534:FRS2 protein, human; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D015363:Quinolones; D034741:RNA, Small Interfering; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D020797:Receptor, Platelet-Derived Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt