Kinase Domain Activation of FGFR2 Yields High-Grade Lung Adenocarcinoma Sensitive to a Pan-FGFR Inhibitor in a Mouse Model of NSCLC
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- Jeremy H. Tchaicha
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Esra A. Akbay
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Abigail Altabef
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Oliver R. Mikse
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Eiki Kikuchi
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Kevin Rhee
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Rachel G. Liao
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Roderick T. Bronson
- 5Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts.
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- Lynette M. Sholl
- 6Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
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- Matthew Meyerson
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Peter S. Hammerman
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
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- Kwok-Kin Wong
- 1Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts.
説明
<jats:title>Abstract</jats:title> <jats:p>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. Cancer Res; 74(17); 4676–84. ©2014 AACR.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 74 (17), 4676-4684, 2014-09-01
American Association for Cancer Research (AACR)