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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / metabolism
-
Apoptosis / drug effects
-
Apoptosis / genetics
-
Benzimidazoles / pharmacology
-
Biomarkers, Tumor / genetics
-
Biomarkers, Tumor / metabolism
-
Carcinogenesis / genetics
-
Cell Line, Tumor
-
Drug Evaluation, Preclinical
-
Humans
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism
-
Myeloid Cell Leukemia Sequence 1 Protein / genetics
-
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
-
Pancreatic Neoplasms / drug therapy*
-
Pancreatic Neoplasms / genetics
-
Pancreatic Neoplasms / metabolism*
-
Phosphorylation / drug effects
-
Proto-Oncogene Proteins c-akt / genetics
-
Proto-Oncogene Proteins c-akt / metabolism
-
Quinolones / pharmacology
-
RNA, Small Interfering / genetics
-
Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors*
-
Receptor, Fibroblast Growth Factor, Type 2 / genetics
-
Receptor, Fibroblast Growth Factor, Type 2 / metabolism*
-
Receptor, Platelet-Derived Growth Factor beta / genetics
-
Receptor, Platelet-Derived Growth Factor beta / metabolism
-
Signal Transduction / drug effects
Substances
-
4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
-
Adaptor Proteins, Signal Transducing
-
Benzimidazoles
-
Biomarkers, Tumor
-
FRS2 protein, human
-
MCL1 protein, human
-
Membrane Proteins
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Quinolones
-
RNA, Small Interfering
-
FGFR2 protein, human
-
Receptor, Fibroblast Growth Factor, Type 2
-
Receptor, Platelet-Derived Growth Factor beta
-
Proto-Oncogene Proteins c-akt