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Ref Type Journal Article
PMID (19381019)
Authors Qing J, Du X, Chen Y, Chan P, Li H, Wu P, Marsters S, Stawicki S, Tien J, Totpal K, Ross S, Stinson S, Dornan D, French D, Wang QR, Stephan JP, Wu Y, Wiesmann C, Ashkenazi A
Title Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice.
Journal The Journal of clinical investigation
Vol 119
Issue 5
Date 2009 May
URL
Abstract Text 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-A 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
R3Mab R3Mab 8 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
R3Mab FGFR3 Inhibitor 13 R3Mab is a monoclonal antibody, which specifically targets FGFR3 to block signaling and tumor growth (PMID: 23657946, PMID: 19381019, PMID: 26269606)
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR3 R248C missense gain of function FGFR3 R248C lies within the extracellular domain of the Fgfr3 protein (UniProt.org). R248C confers a gain of function to the Fgfr3 protein as demonstrated by constitutive ligand-independent cell proliferation (PMID: 19381019) and increased activation of the Mapk signaling pathway (PMID: 24626198).
FGFR3 S249C missense gain of function FGFR3 S249C lies within the linker region between IgD2 and IgD3 of the Fgfr3 protein (PMID: 19381019). S249C confers a gain of function to the Fgfr3 protein as demonstrated by stabilized homodimer formation and constitutive phosphorylation in vitro (PMID: 17384684), constitutive ligand-independent cell proliferation in culture (PMID: 19381019, PMID: 29533785) and increased Akt signaling (PMID: 31316618). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 G372C Advanced Solid Tumor sensitive R3Mab Preclinical - Cell culture Actionable In a preclinical study, R3Mab inhibited ligand-dependent proliferation in cells expressing FGFR3 G372C (PMID: 19381019). 19381019
FGFR3 S249C bladder carcinoma sensitive R3Mab Preclinical - Cell line xenograft Actionable In a preclinical study, R3Mab decreased dimer formation and constitutive activation of FGFR3 S249C, and inhibited growth of bladder cancer cell lines harboring FGFR3 S249C in culture and in xenograft models (PMID: 19381019). 19381019
FGFR3 Y375C Advanced Solid Tumor sensitive R3Mab Preclinical - Cell culture Actionable In a preclinical study, R3Mab inhibited ligand-dependent proliferation of cells expressing FGFR3 Y375C in culture (PMID: 19381019). 19381019
FGFR3 S249C Advanced Solid Tumor sensitive R3Mab Preclinical - Cell culture Actionable In a preclinical study, R3Mab inhibited proliferation of transformed cells expressing FGFR3 S249C in culture (PMID: 19381019). 19381019
FGFR3 K652E Advanced Solid Tumor sensitive R3Mab Preclinical - Cell culture Actionable In a preclinical study, R3Mab inhibited ligand-dependent cell proliferation in cells expressing FGFR3 K652E in culture (PMID: 19381019). 19381019
FGFR3 R248C Advanced Solid Tumor sensitive R3Mab Preclinical - Cell culture Actionable In a preclinical study, R3Mab inhibited ligand-independent proliferation induced by FGFR3 R248C in cultured cells (PMID: 19381019). 19381019
FGFR3 wild-type bladder carcinoma sensitive R3Mab Preclinical - Cell line xenograft Actionable In a preclinical study, R3Mab decreased wild-type FGFR3 activation, thereby inhibited cell proliferation of FGFR3 wild-type human bladder cancer cells in culture and in cell line xenograft models (PMID: 19381019). 19381019