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Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma
Author(s) -
Paterson Joshua L.,
Li Zhihua,
Wen XiaoYan,
MasihKhan Esther,
Chang Hong,
Pollett Jonathan B.,
Trudel Suzanne,
Stewart A. Keith
Publication year - 2004
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2004.04814.x
Subject(s) - fibroblast growth factor receptor 3 , microbiology and biotechnology , cancer research , multiple myeloma , biology , cell culture , chromosomal translocation , tyrosine kinase , fibroblast growth factor receptor , fibroblast growth factor , signal transduction , receptor , immunology , biochemistry , genetics , gene
Summary 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 G 0 /G 1 cells, and 4·5‐fold increase in apoptotic cells after 72 h treatment with 10 μ mol/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.