Targeting Fibroblast Growth Factor Receptor (FGFR) with BGJ398 in a Gastric Cancer Model.

Abstract

AIM:

To assess the efficacy of targeting fibroblast growth factor receptor (FGFR) with the pan-FGFR inhibitor BGJ398 in a gastric cancer (GC) model.

MATERIALS AND METHODS:

Expression of FGFRs was determined in GC cell lines (KKLS, MKN-45, TMK-1). Impact of the FGFR inhibitor BGJ398 on growth, motility, signaling, expression of transcription factors and secretion of vascular endothelial growth factor-A (VEGFA) was determined in vitro. Results were validated in subcutaneous tumor models.

RESULTS:

In vitro, FGFR inhibition was most effective in KKLS cells (high FGFR1, FGFR2IIIc, no FGFR2IIIb expression) with inhibition of growth, motility, signaling, c-MYC expression and VEGFA secretion. BGJ398 showed some activity in MKN-45 cells (intermediate FGFR1, high FGFR2IIIb, low FGFR2IIIc expression), while TMK-1 cells (low FGFR1, no FGFR2IIIb and FGFR2IIIc expression) did not respond. Results were confirmed in vivo with strongest efficacy on growth in KKLS tumors and only minor impairment of TMK-1 lesions.

CONCLUSION:

Efficacy of FGFR inhibition is dependent on FGFR1 and FGFR2IIIc expression in GC models.

• Authors: Katharina Schmidt, Christian Moser, Claus Hellerbrand, Derek Zieker, Christine Wagner, Julia Redekopf, Hans J Schlitt, Edward K Geissler, Sven A Lang
• Journal: Anticancer research (Anticancer Res) Vol. 35 Issue 12 Pg. 6655-65 (Dec 2015) ISSN: 1791-7530 [Electronic] Greece
• PMID: 26637881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Chemical References

• Phenylurea Compounds
• Pyrimidines
• infigratinib
• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Cell Line, Tumor
• Cell Proliferation
• Humans
• Phenylurea Compounds (metabolism)
• Pyrimidines (metabolism)
• Receptor, Fibroblast Growth Factor, Type 1 (metabolism)
• Stomach Neoplasms (genetics, metabolism)