Preclinical Studies of Fibroblast Growth Factor Receptor 3 as a Therapeutic Target in Multiple Myeloma

Br J Haematol. 2004 Mar;124(5):595-603. doi: 10.1111/j.1365-2141.2004.04814.x.

Abstract

Dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the translocation t(4;14)(p16;q32) occurs in 15% of multiple myeloma (MM) patients and confers a growth and survival advantage to malignant plasma cells. As FGFR3 is a molecular target, we assessed the therapeutic potential of the FGFR-specific tyrosine kinase inhibitors SU5402 and SU10991 in MM. SU5402 inhibited FGFR3 phosphorylation in vitro and in murine MM tumour models. B cells dependent on FGFR3 for survival were specifically sensitive to SU5402. A panel of 11 human myeloma cell lines was studied, five bearing the t(4;14) translocation. The KMS11 human myeloma cell line, which expresses constitutively active mutant FGFR3, displayed an 85% decrease in S-phase cells, a 95% increase in G0/G1 cells, and 4.5-fold increase in apoptotic cells after 72 h treatment with 10 micromol/l SU5402. Activated extracellular signal-regulated kinases 1 and 2 and signal transducer and activator of transcription 3 were rapidly down-regulated after SU5402 treatment. In human myeloma cell lines expressing wild-type FGFR3 the stimulating effect of aFGF ligand was abrogated by SU5402 treatment. Myeloma cells lacking the t(4;14) or with the t(4;14) and a secondary RAS mutation did not respond to therapy. These findings support the development of clinical trials of early intervention with FGFR3 inhibitors in t(4;14) myeloma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carrier Proteins / antagonists & inhibitors
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cell Line, Tumor
  • DNA-Binding Proteins / antagonists & inhibitors
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Multiple Myeloma / pathology
  • Mutation / genetics
  • Phosphorylation
  • Protein-Tyrosine Kinases*
  • Pyrroles / pharmacology*
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Repressor Proteins / antagonists & inhibitors
  • STAT3 Transcription Factor
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / antagonists & inhibitors

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Pyrroles
  • Receptors, Fibroblast Growth Factor
  • Repressor Proteins
  • SOCS1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • SU 5402
  • Socs1 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • FGFR3 protein, human
  • Fgfr3 protein, mouse
  • Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 3
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases