Small Molecule FGF Receptor Inhibitors Block FGFR-dependent Urothelial Carcinoma Growth in Vitro and in Vivo

Br J Cancer. 2011 Jan 4;104(1):75-82. doi: 10.1038/sj.bjc.6606016. Epub 2010 Nov 30.

Abstract

Background: Activating mutations of FGFR3 are frequently identified in superficial urothelial carcinoma (UC) and increased expression of FGFR1 and FGFR3 are common in both superficial and invasive UC.

Methods: The effects of inhibition of receptor activity by three small molecule inhibitors (PD173074, TKI-258 and SU5402) were investigated in a panel of bladder tumour cell lines with known FGFR expression levels and FGFR3 mutation status.

Results: All inhibitors prevented activation of FGFR3, and inhibited downstream MAPK pathway signalling. Response was related to FGFR3 and/or FGFR1 expression levels. Cell lines with the highest levels of FGFR expression showed the greatest response and little or no effect was measured in normal human urothelial cells or in UC cell lines with activating RAS gene mutations. In sensitive cell lines, the drugs induced cell cycle arrest and/or apoptosis. IC(50) values for PD173074 and TKI-258 were in the nanomolar concentration range compared with micromolar concentrations for SU5402. PD173074 showed the greatest effects in vitro and in vivo significantly delayed the growth of subcutaneous bladder tumour xenografts.

Conclusion: These results indicate that inhibition of FGFR1 and wild-type or mutant FGFR3 may represent a useful therapeutic approach in patients with both non-muscle invasive and muscle invasive UC.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Benzimidazoles / therapeutic use*
  • Blotting, Western
  • Carcinoma, Transitional Cell / metabolism
  • Carcinoma, Transitional Cell / pathology
  • Carcinoma, Transitional Cell / prevention & control*
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Humans
  • Immunoenzyme Techniques
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mutation / genetics
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrimidines / therapeutic use*
  • Pyrroles / therapeutic use*
  • Quinolones / therapeutic use*
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 3 / metabolism
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / prevention & control*
  • Urothelium / drug effects
  • Urothelium / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • 4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
  • Benzimidazoles
  • PD 173074
  • Pyrimidines
  • Pyrroles
  • Quinolones
  • SU 5402
  • Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 3