Inhibition of fibroblast growth factor receptor 3-dependent lung adenocarcinoma with a human monoclonal antibody

Activating mutations in fibroblast growth factor receptor 3 (FGFR3) have been identified in multiple types of human cancer and in congenital birth defects. In human lung cancer, fibroblast growth factor 9 (FGF9), a high-affinity ligand for FGFR3, is overexpressed in 10% of primary resected non-small...

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Published in:	Disease models & mechanisms 2016-05, Vol.9 (5), p.563-571
Main Authors:	Yin, Yongjun, Ren, Xiaodi, Smith, Craig, Guo, Qianxu, Malabunga, Maria, Guernah, Ilhem, Zhang, Yiwei, Shen, Juqun, Sun, Haijun, Chehab, Nabil, Loizos, Nick, Ludwig, Dale L, Ornitz, David M
Format:	Article
Language:	eng
Subjects:	Adenocarcinoma Adenocarcinoma - drug therapy Adenocarcinoma - pathology Adenocarcinoma of Lung Animals Antibodies, Blocking - pharmacology Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal - therapeutic use Bladder Bronchioles - pathology Cancer Cell growth Cell Proliferation - drug effects FGFR3 Fibroblast Growth Factor 9 - metabolism Fibroblast growth factor receptor 3 Fibroblasts Flow cytometry Growth factors Histology Humans Hyperplasia Inhibitory monoclonal antibody Ligands Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - pathology Lungs Macrophages - drug effects Macrophages - metabolism Macrophages - pathology Medical prognosis Mice Monoclonal antibodies Multiple myeloma Mutation NSCLC Proteins Pulmonary Alveoli - pathology Receptor, Fibroblast Growth Factor, Type 3 - metabolism Surfactants Tumorigenesis Tumors
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Summary:	Activating mutations in fibroblast growth factor receptor 3 (FGFR3) have been identified in multiple types of human cancer and in congenital birth defects. In human lung cancer, fibroblast growth factor 9 (FGF9), a high-affinity ligand for FGFR3, is overexpressed in 10% of primary resected non-small cell lung cancer (NSCLC) specimens. Furthermore, in a mouse model where FGF9 can be induced in lung epithelial cells, epithelial proliferation and ensuing tumorigenesis is dependent on FGFR3. To develop new customized therapies for cancers that are dependent on FGFR3 activation, we have used this mouse model to evaluate a human monoclonal antibody (D11) with specificity for the extracellular ligand-binding domain of FGFR3, that recognizes both human and mouse forms of the receptor. Here, we show that D11 effectively inhibits signaling through FGFR3 in vitro, inhibits the growth of FGFR3-dependent FGF9-induced lung adenocarcinoma in mice, and reduces tumor-associated morbidity. Given the potency of FGF9 in this mouse model and the absolute requirement for signaling through FGFR3, this study validates the D11 antibody as a potentially useful and effective reagent for treating human cancers or other pathologies that are dependent on activation of FGFR3.
ISSN:	1754-8403 1754-8411