Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma.

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.

• Authors: Joshua L Paterson, Zhihua Li, Xiao-Yan Wen, Esther Masih-Khan, Hong Chang, Jonathan B Pollett, Suzanne Trudel, A Keith Stewart
• Journal: British journal of haematology (Br J Haematol) Vol. 124 Issue 5 Pg. 595-603 (Mar 2004) ISSN: 0007-1048 [Print] England
• PMID: 14871245 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, genetics, 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)