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FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma
Yaron Hadari, Joseph Schlessinger
Yaron Hadari, Joseph Schlessinger
Published April 20, 2009
Citation Information: J Clin Invest. 2009;119(5):1077-1079. https://doi.org/10.1172/JCI38948.
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Commentary Article has an altmetric score of 6

FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma

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Abstract

Gain-of-function mutations in FGF receptor 3 (FGFR3) have been implicated in severe skeletal dysplasias and in a variety of cancers. In their study in this issue of the JCI, Qing et al. used specific shRNA probes to demonstrate that FGFR3 functions as an important driver of bladder carcinoma cell proliferation (see the related article beginning on page 1216). A unique anti-FGFR3 mAb was shown to exhibit antitumor activity in human bladder carcinoma cells in vitro and in mouse bladder cancer or multiple myeloma xenograft tumor models bearing either wild-type or mutant FGFR3. These results suggest that clinical development of anti-FGFR3 mAbs should be considered for targeted therapy of cancer and other diseases.

Authors

Yaron Hadari, Joseph Schlessinger

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Figure 1

Potential mechanism of inhibition of the activity of disulfide-linked oncogenic FGFR3 mutants by treatment with an anti-FGFR3 mAb (R3Mab).

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Potential mechanism of inhibition of the activity of disulfide-linked on...
Oncogenic FGFR3 mutants R248C and S249C remain monomeric as long as they remain inside the cell in the endoplasmic reticulum and other intracellular compartments. Upon migration to the cell surface and exposure to the oxidative extracellular environment, disulfide-linked activated dimers of FGFR3 are formed, resulting in tyrosine phosphorylation and triggering of intracellular signaling pathways that result in bladder cell carcinoma proliferation (A). In their study in this issue of the JCI, Qing et al. (7) report that binding of their anti-FGFR3 mAb (R3Mab) to D2 and D3 of the extracellular ligand-binding region of FGFR3 before intermolecular disulfide linkages are formed prevents formation of disulfide-linked FGFR3 dimers with constitutively stimulated tyrosine kinase activity, resulting in the inhibition of bladder cell carcinoma proliferation and of tumor formation (B). Cysteines of R248C or S249C FGFR3 are shown in magenta. The stimulated tyrosine kinase domain is shown in red.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 3 patents
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