Targeting FGFR3 in Multiple Myeloma: Inhibition of t(4;14)-positive Cells by SU5402 and PD173074

Leukemia. 2004 May;18(5):962-6. doi: 10.1038/sj.leu.2403347.

Abstract

The t(4;14)(p16.3;q32), associated with 10-20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Chromosomes, Human, Pair 14*
  • Chromosomes, Human, Pair 4*
  • Humans
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / genetics
  • Protein-Tyrosine Kinases*
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Pyrroles / pharmacology*
  • Pyrroles / therapeutic use
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
  • Translocation, Genetic*

Substances

  • PD 173074
  • Pyrimidines
  • Pyrroles
  • Receptors, Fibroblast Growth Factor
  • SU 5402
  • FGFR3 protein, human
  • Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 3