1. Mouse models for ROS1-fusion-positive lung cancers and their application to the analysis of multikinase inhibitor efficiency.
- Author
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Inoue, Maki, Hideaki Toki, Matsui, Junko, Yuki Togashi, Dobashi, Akito, Fukumura, Ryutaro, Yoichi Gondo, Osamu Minowa, Norio Tanaka, Seiichi Mori, Kengo Takeuchi, and Tetsuo Noda
- Subjects
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GENE fusion , *PROTEIN-tyrosine kinases , *KINASE inhibitors , *LUNG cancer & genetics , *PROTO-oncogenes , *IN vivo studies , *LABORATORY mice - 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 earlyonset 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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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