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Published on: September 30, 2019
Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma
Joshua L Paterson1, Zhihua Li, Xiao-Yan Wen
1Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
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.
Insights
Fibroblast growth factor receptor 3 (FGFR3) inhibitors like SU5402 show therapeutic potential for multiple myeloma (MM) with the t(4;14) translocation. This targeted therapy effectively reduced cancer cell proliferation and increased apoptosis in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The translocation t(4;14) in 15% of multiple myeloma (MM) patients leads to dysregulation of fibroblast growth factor receptor 3 (FGFR3).
- Dysregulated FGFR3 provides a significant growth and survival advantage to malignant plasma cells, making it a key molecular target.
Purpose of the Study:
- To evaluate the therapeutic potential of FGFR-specific tyrosine kinase inhibitors, SU5402 and SU10991, in multiple myeloma (MM).
- To investigate the efficacy of FGFR3 inhibition in preclinical MM models, particularly in the context of the t(4;14) translocation.
Main Methods:
- In vitro and murine MM tumor models were used to assess the effects of SU5402 on FGFR3 phosphorylation.
- Eleven human myeloma cell lines, including five with the t(4;14) translocation, were treated with SU5402 to evaluate its impact on cell cycle, apoptosis, and signaling pathways.
- The response to SU5402 was analyzed in cell lines with wild-type FGFR3, mutant FGFR3, and those with additional mutations like RAS.
Main Results:
- SU5402 effectively inhibited FGFR3 phosphorylation in vitro and in vivo.
- The KMS11 cell line with mutant FGFR3 showed significant cell cycle arrest, increased apoptosis, and down-regulation of key signaling proteins (ERK1/2, STAT3) after SU5402 treatment.
- FGFR3-dependent B cells were specifically sensitive to SU5402, while myeloma cells lacking t(4;14) or with secondary RAS mutations did not respond.
Conclusions:
- FGFR3 inhibitors, such as SU5402, demonstrate significant preclinical efficacy against multiple myeloma with the t(4;14) translocation.
- These findings strongly support the development of clinical trials for early intervention with FGFR3 inhibitors in patients with t(4;14) multiple myeloma.
