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

Yongjun Yin, Xiaodi Ren, Craig Smith, Qianxu Guo, Maria Malabunga, Ilhem Guernah, Yiwei Zhang, Juqun Shen, Haijun Sun, Nabil Chehab, Nick Loizos, Dale L. Ludwig, David M. Ornitz

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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 tumorassociated 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.

Original languageEnglish
Pages (from-to)563-571
Number of pages9
JournalDMM Disease Models and Mechanisms
Volume9
Issue number5
DOIs
StatePublished - May 1 2016

Keywords

  • Adenocarcinoma
  • FGFR3
  • Fibroblast growth factor receptor 3
  • Inhibitory monoclonal antibody
  • Lung cancer
  • NSCLC

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