Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models

H. Zhang, B. L. Hylander, C. Levea, E. A. Repasky, R. M. Straubinger, Alex Adjei, Wen Wee Ma

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.Conclusion: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.

Original languageEnglish (US)
Pages (from-to)320-329
Number of pages10
JournalBritish Journal of Cancer
Volume110
Issue number2
DOIs
StatePublished - Jan 21 2014
Externally publishedYes

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Fibroblast Growth Factor Receptors
Pancreatic Neoplasms
Small Interfering RNA
Neoplasms
Biomarkers
Phosphorylation
Messenger RNA
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
Pancreas
Carcinogenesis
Therapeutics
Ligands
Cell Line

Keywords

  • fibroblast growth factor receptor
  • pancreatic cancer
  • predictive biomarker
  • tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models. / Zhang, H.; Hylander, B. L.; Levea, C.; Repasky, E. A.; Straubinger, R. M.; Adjei, Alex; Ma, Wen Wee.

In: British Journal of Cancer, Vol. 110, No. 2, 21.01.2014, p. 320-329.

Research output: Contribution to journalArticle

Zhang, H. ; Hylander, B. L. ; Levea, C. ; Repasky, E. A. ; Straubinger, R. M. ; Adjei, Alex ; Ma, Wen Wee. / Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models. In: British Journal of Cancer. 2014 ; Vol. 110, No. 2. pp. 320-329.
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