Abstract
The t(4;14) translocation that occurs uniquely in a subset (15%) of patients with multiple myeloma (MM) results in the ectopic expression of the receptor tyrosine kinase (RTK), fibroblast growth factor receptor 3 (FGFR3). Inhibition of activated FGFR3 in MM cells induces apoptosis, validating FGFR3 as a therapeutic target in t(4;14) MM and encouraging the clinical development of FGFR3 inhibitors for the treatment of these patients, who have a poor prognosis. We describe here the characterization of a novel, small-molecule inhibitor of class III, IV, and V RTKs, CHIR-258, as an inhibitor of FGFR3. CHIR-258 potently inhibits FGFR3 with an inhibitory concentration of 50% (IC50) of 5 nM in in vitro kinase assays and selectively inhibited the growth of B9 cells and human myeloma cell lines expressing wild-type (WT) or activated mutant FGFR3. In responsive cell lines, CHIR-258 induced cytostatic and cytotoxic effects. Importantly, addition of interleukin 6 (IL-6) or insulin growth factor 1 (IGF-1) or coculture on stroma did not confer resistance to CHIR-258. In primary myeloma cells from t(4;14) patients, CHIR-258 inhibited downstream extracellular signal-regulated kinase (ERK) 1/2 phosphorylation with an associated cytotoxic response. Finally, therapeutic efficacy of CHIR-258 was demonstrated in a xenograft mouse model of FGFR3 MM. These studies support the clinical evaluation of CHIR-258 in MM.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzimidazoles / pharmacology*
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Cell Division / drug effects
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Cell Line, Tumor
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Cell Transformation, Neoplastic / drug effects
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Dexamethasone / toxicity
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Drug Interactions
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Female
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Glucocorticoids / toxicity
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Humans
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Insulin-Like Growth Factor I / pharmacology
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Interleukin-6 / pharmacology
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Macrophage Colony-Stimulating Factor / pharmacology
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Mice
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Mice, Inbred Strains
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / metabolism*
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / metabolism
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Quinolones / 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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Receptors, Fibroblast Growth Factor / metabolism
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Stromal Cells / cytology
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Xenograft Model Antitumor Assays
Substances
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4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one
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Benzimidazoles
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Glucocorticoids
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Interleukin-6
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Protein Kinase Inhibitors
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Quinolones
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Receptors, Fibroblast Growth Factor
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Insulin-Like Growth Factor I
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Dexamethasone
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Macrophage Colony-Stimulating Factor
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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