Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice
Open Access
- 1 May 2009
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 119 (5), 1216-1229
- https://doi.org/10.1172/jci38017
Abstract
Overexpression of FGF receptor 3 (FGFR3) is implicated in the development of t(4;14)-positive multiple myeloma. While FGFR3 is frequently overexpressed and/or activated through mutations in bladder cancer, the functional importance of FGFR3 and its potential as a specific therapeutic target in this disease have not been elucidated in vivo. Here we report that inducible knockdown of FGFR3 in human bladder carcinoma cells arrested cell-cycle progression in culture and markedly attenuated tumor progression in xenografted mice. Further, we developed a unique antibody (R3Mab) that inhibited not only WT FGFR3, but also various mutants of the receptor, including disulfide-linked cysteine mutants. Biochemical analysis and 2.1-Å resolution crystallography revealed that R3Mab bound to a specific FGFR3 epitope that simultaneously blocked ligand binding, prevented receptor dimerization, and induced substantial conformational changes in the receptor. R3Mab exerted potent antitumor activity against bladder carcinoma and t(4;14)-positive multiple myeloma xenografts in mice by antagonizing FGFR3 signaling and eliciting antibody-dependent cell-mediated cytotoxicity (ADCC). These studies provide in vivo evidence demonstrating an oncogenic role of FGFR3 in bladder cancer and support antibody-based targeting of FGFR3 in hematologic and epithelial cancers driven by WT or mutant FGFR3.Keywords
This publication has 49 references indexed in Scilit:
- Antitumor activity of fibroblast growth factor receptor 3–specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosisMolecular Cancer Therapeutics, 2008
- FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancerThe Journal of Pathology, 2007
- Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancerOncogene, 2007
- Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3bCarcinogenesis: Integrative Cancer Research, 2005
- Mechanisms underlying differential responses to FGF signalingCytokine & Growth Factor Reviews, 2005
- The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3Oncogene, 2003
- Clinical and biologic implications of recurrent genomic aberrations in myelomaBlood, 2003
- Frequent FGFR3 mutations in urothelial papillomaThe Journal of Pathology, 2002
- Mutations of the BRAF gene in human cancerNature, 2002
- NMDA receptor redox sites: are they targets for selective neuronal protection?Trends in Pharmacological Sciences, 1995