title: Mouse models for ROS1-fusion-positive lung cancers and their application to the analysis of multikinase inhibitor efficiency.
abstract: ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1-2% of human non-small cell lung cancer cases. More than 10 distinct ROS1-fusion genes, including break-point variants, have been identified to date. In this study, to investigate the in vivo oncogenic activities of one of the most frequently detected fusions, CD74-ROS1, as well as another SDC4-ROS1 fusion that has also been reported in several studies, we generated transgenic (TG) mouse strains that express either of the two ROS1-fusion genes specifically in lung alveolar type II cells. Mice in all TG lines developed tumorigenic nodules in the lung, and a few strains of both TG mouse lines demonstrated early-onset nodule development (multiple tumor lesions present in the lung at 2-4 weeks after birth); therefore, these two strains were selected for further investigation. Tumors developed progressively in the untreated TG mice of both lines, whereas those receiving oral administration of an ALK/MET/ROS1 inhibitor, crizotinib, and an ALK/ROS1 inhibitor, ASP3026, showed marked reduction in the tumor burden. Collectively, these data suggest that each of these two ROS1-fusion genes acts as a driver for the pathogenesis of lung adenocarcinoma in vivo The TG mice developed in this study are expected to serve as valuable tools for exploring novel therapeutic agents against ROS1-fusion-positive lung cancer.
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, Tsukuba 305-0074, Japan, Division of Cell Biology.
authors.forename: Maki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, Tsukuba 305-0074, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Toki
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, Tsukuba 305-0074, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Matsui
authors.affiliation: Pathology Project for Molecular Targets and Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Togashi
authors.affiliation: Pathology Project for Molecular Targets and.
authors.forename: Akito
authors.initials: A
authors.lastname: Dobashi
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba 305-0074, Japan and.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Fukumura
authors.affiliation: Mutagenesis and Genomics Team, RIKEN BioResource Center, Tsukuba 305-0074, Japan and.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Gondo
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, Tsukuba 305-0074, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Minowa
authors.affiliation: Project for Development of Innovative Research on Cancer Therapeutics, The Genome Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Project for Development of Innovative Research on Cancer Therapeutics, The Genome Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mori
authors.affiliation: Pathology Project for Molecular Targets and Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Team for Advanced Development and Evaluation of Human Disease Models, RIKEN BioResource Center, Tsukuba 305-0074, Japan, Division of Cell Biology, tnoda@jfcr.or.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D000077547:Crizotinib; D050939:Gene Fusion; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D053671:Syndecan-4 / Q000235:genetics; D014227:Triazines / Q000494:pharmacology
chemical_list: C000595153:ASP3026; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; C508304:SDC4 protein, human; D013450:Sulfones; D053671:Syndecan-4; D014227:Triazines; C045084:invariant chain; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human