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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Carrier Proteins / antagonists & inhibitors
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Cell Cycle / drug effects
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Cell Division / drug effects
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Cell Line, Tumor
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DNA-Binding Proteins / antagonists & inhibitors
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Humans
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Intracellular Signaling Peptides and Proteins*
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Mice
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Mice, Inbred BALB C
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / genetics
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Multiple Myeloma / pathology
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Mutation / genetics
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Phosphorylation
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Protein-Tyrosine Kinases*
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Pyrroles / pharmacology*
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Receptor, Fibroblast Growth Factor, Type 3
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
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Repressor Proteins / antagonists & inhibitors
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STAT3 Transcription Factor
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / antagonists & inhibitors
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Pyrroles
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Receptors, Fibroblast Growth Factor
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Repressor Proteins
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SOCS1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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SU 5402
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Socs1 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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FGFR3 protein, human
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Fgfr3 protein, mouse
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Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 3
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases