title: Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a Pan-FGFR inhibitor in a mouse model of NSCLC.
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.
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Ludwig Institute for Cancer, Cambridge, Massachusetts.
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Tchaicha
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Ludwig Institute for Cancer, Cambridge, Massachusetts.
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Ludwig Institute for Cancer, Cambridge, Massachusetts.
authors.forename: Abigail
authors.initials: A
authors.lastname: Altabef
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Ludwig Institute for Cancer, Cambridge, Massachusetts.
authors.forename: Oliver R
authors.initials: OR
authors.lastname: Mikse
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Ludwig Institute for Cancer, Cambridge, Massachusetts.
authors.forename: Eiki
authors.initials: E
authors.lastname: Kikuchi
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Ludwig Institute for Cancer, Cambridge, Massachusetts.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rhee
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. The Broad Institute, Cambridge, Massachusetts.
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Liao
authors.affiliation: Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. The Broad Institute, Cambridge, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. The Broad Institute, Cambridge, Massachusetts. kwong1@partners.org peter_hammerman@dfci.harvard.edu.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Ludwig Institute for Cancer, Cambridge, Massachusetts. Belfer Institute for Applied Cancer Science, Boston, Massachusetts. kwong1@partners.org peter_hammerman@dfci.harvard.edu.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2