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

Cancer Res
Authors
Keywords
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.

Year of Publication
2014
Journal
Cancer Res
Volume
74
Issue
17
Pages
4676-84
Date Published
2014 Sep 01
ISSN
1538-7445
URL
DOI
10.1158/0008-5472.CAN-13-3218
PubMed ID
25035393
PubMed Central ID
PMC4154986
Links
Grant list
P50CA090578 / CA / NCI NIH HHS / United States
CA166480 / CA / NCI NIH HHS / United States
R01 CA122794 / CA / NCI NIH HHS / United States
K08 CA163677 / CA / NCI NIH HHS / United States
1K08CA163677 / CA / NCI NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
CA163896 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
R01 CA163896 / CA / NCI NIH HHS / United States
R01 CA166480 / CA / NCI NIH HHS / United States
CA122794 / CA / NCI NIH HHS / United States
R01 CA140594 / CA / NCI NIH HHS / United States
CA140594 / CA / NCI NIH HHS / United States
CA120964 / CA / NCI NIH HHS / United States
P50 CA090578 / CA / NCI NIH HHS / United States
CA154303 / CA / NCI NIH HHS / United States