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

Joshua L. Paterson, Zhihua Li, Xiao Yan Wen, Esther Masih-Khan, Hong Chang, Jonathan B. Pollett, Suzanne Trudel, Alexander Keith Stewart

Research output: Contribution to journalArticle

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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 G 0/G 1 cells, and 4.5-fold increase in apoptotic cells after 72 h treatment with 10 μmol/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.

Original languageEnglish (US)
Pages (from-to)595-603
Number of pages9
JournalBritish Journal of Haematology
Volume124
Issue number5
DOIs
StatePublished - Mar 2004
Externally publishedYes

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Receptor, Fibroblast Growth Factor, Type 3
Multiple Myeloma
Cell Line
Therapeutics
STAT3 Transcription Factor
Gastrin-Secreting Cells
Mitogen-Activated Protein Kinase 3
Survival
Mitogen-Activated Protein Kinase 1
Plasma Cells
S Phase
Protein-Tyrosine Kinases
SU 5402
B-Lymphocytes
Phosphorylation
Clinical Trials
Ligands
Mutation

Keywords

  • FGFR3
  • Multiple myeloma
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Hematology

Cite this

Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. / Paterson, Joshua L.; Li, Zhihua; Wen, Xiao Yan; Masih-Khan, Esther; Chang, Hong; Pollett, Jonathan B.; Trudel, Suzanne; Stewart, Alexander Keith.

In: British Journal of Haematology, Vol. 124, No. 5, 03.2004, p. 595-603.

Research output: Contribution to journalArticle

Paterson, Joshua L. ; Li, Zhihua ; Wen, Xiao Yan ; Masih-Khan, Esther ; Chang, Hong ; Pollett, Jonathan B. ; Trudel, Suzanne ; Stewart, Alexander Keith. / Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. In: British Journal of Haematology. 2004 ; Vol. 124, No. 5. pp. 595-603.
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