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

• Published in: British journal of cancer Vol. 110; no. 2; pp. 320 - 329
• Main Authors: Zhang, H, Hylander, B L, LeVea, C, Repasky, E A, Straubinger, R M, Adjei, A A, Ma, W W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2014; Nature Publishing Group
• Subjects: 631/80/86; 692/699/67/1059/602; 692/699/67/1504/1713; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Apoptosis - drug effects; Apoptosis - genetics; Benzimidazoles - pharmacology; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinogenesis - genetics; Cell Line, Tumor; Drug Evaluation, Preclinical; Drug Resistance; Epidemiology; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Oncology; Pancreatic cancer; 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; 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; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Translational Therapeutics; Tumors; pancreatic cancer; predictive biomarker; tyrosine kinase inhibitor; fibroblast growth factor receptor; Fibroblast growth factor; Tyrosine kinase inhibitor; Biological marker; Malignant tumor; Signal transduction; Growth factor receptor; Cancerology; Pancreas cancer; Digestive diseases; Models; Cancer; Pancreatic disease
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.754

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 PDGFR β . 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.