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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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical investigation	119	5	2009 May	1216-29	J Clin Invest

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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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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 results in stabilized homodimer formation and constitutive Fgfr3 phosphorylation in vitro (PMID: 17384684), ligand-independent cell proliferation in culture (PMID: 19381019, PMID: 29533785), increased Akt signaling (PMID: 31316618), a growth advantage relative to wild-type Fgfr3 in a competition assay, and increased transformation activity in cultured cells (PMID: 34272467).	Y

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR3 S249C	bladder carcinoma	sensitive	Vofatamab	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Vofatamab (B-701) 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 wild-type	bladder carcinoma	sensitive	Vofatamab	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Vofatamab (B-701) 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
FGFR3 G372C	Advanced Solid Tumor	sensitive	Vofatamab	Preclinical - Cell culture	Actionable	In a preclinical study, Vofatamab (B-701) inhibited ligand-dependent proliferation in cells expressing FGFR3 G372C (PMID: 19381019).	19381019
FGFR3 K652E	Advanced Solid Tumor	sensitive	Vofatamab	Preclinical - Cell culture	Actionable	In a preclinical study, Vofatamab (B-701) inhibited ligand-dependent cell proliferation in cells expressing FGFR3 K652E in culture (PMID: 19381019).	19381019
FGFR3 R248C	Advanced Solid Tumor	sensitive	Vofatamab	Preclinical - Cell culture	Actionable	In a preclinical study, Vofatamab (B-701) inhibited ligand-independent proliferation induced by FGFR3 R248C in cultured cells (PMID: 19381019).	19381019
FGFR3 S249C	Advanced Solid Tumor	sensitive	Vofatamab	Preclinical - Cell culture	Actionable	In a preclinical study, Vofatamab (B-701) inhibited proliferation of transformed cells expressing FGFR3 S249C in culture (PMID: 19381019).	19381019
FGFR3 Y375C	Advanced Solid Tumor	sensitive	Vofatamab	Preclinical - Cell culture	Actionable	In a preclinical study, Vofatamab (B-701) inhibited ligand-dependent proliferation of cells expressing FGFR3 Y375C in culture (PMID: 19381019).	19381019

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