Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a Pan-FGFR inhibitor in a mouse model of NSCLC

Cancer Res. 2014 Sep 1;74(17):4676-84. doi: 10.1158/0008-5472.CAN-13-3218. Epub 2014 Jul 17.

Abstract

Somatic mutations in FGFR2 are present in 4% to 5% of patients diagnosed with non-small cell lung cancer (NSCLC). Amplification and mutations in FGFR genes have been identified in patients with NSCLCs, and clinical trials are testing the efficacy of anti-FGFR therapies. FGFR2 and other FGFR kinase family gene alterations have been found in both lung squamous cell carcinoma and lung adenocarcinoma, although mouse models of FGFR-driven lung cancers have not been reported. Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2. Combined with p53 ablation, primary grade 3/4 adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells. Tumors were acutely sensitive to pan-FGFR inhibition. This is the first FGFR2-driven lung cancer GEMM, which can be applied across different cancer indications in a preclinical setting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma of Lung
  • Animals
  • Animals, Genetically Modified / genetics
  • Animals, Genetically Modified / metabolism
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Disease Models, Animal
  • Female
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mutation / drug effects
  • Mutation / genetics
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Tumor Suppressor Protein p53
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2