title: Mouse model for ROS1-rearranged lung cancer.
abstract: Genetic rearrangement of the ROS1 receptor tyrosine kinase was recently identified as a distinct molecular signature for human non-small cell lung cancer (NSCLC). However, direct evidence of lung carcinogenesis induced by ROS1 fusion genes remains to be verified. The present study shows that EZR-ROS1 plays an essential role in the oncogenesis of NSCLC harboring the fusion gene. EZR-ROS1 was identified in four female patients of lung adenocarcinoma. Three of them were never smokers. Interstitial deletion of 6q22-q25 resulted in gene fusion. Expression of the fusion kinase in NIH3T3 cells induced anchorage-independent growth in vitro, and subcutaneous tumors in nude mice. This transforming ability was attributable to its kinase activity. The ALK/MET/ROS1 kinase inhibitor, crizotinib, suppressed fusion-induced anchorage-independent growth of NIH3T3 cells. Most importantly, established transgenic mouse lines specifically expressing EZR-ROS1 in lung alveolar epithelial cells developed multiple adenocarcinoma nodules in both lungs at an early age. These data suggest that the EZR-ROS1 is a pivotal oncogene in human NSCLC, and that this animal model could be valuable for exploring therapeutic agents against ROS1-rearranged lung cancer.
authors: Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors: Yasuhito
authors: Y
authors: Arai
authors: Yasushi
authors: Y
authors: Totoki
authors: Hiroyuki
authors: H
authors: Takahashi
authors: Hiromi
authors: H
authors: Nakamura
authors: Natsuko
authors: N
authors: Hama
authors: Takashi
authors: T
authors: Kohno
authors: Koji
authors: K
authors: Tsuta
authors: Akihiko
authors: A
authors: Yoshida
authors: Hisao
authors: H
authors: Asamura
authors: Michihiro
authors: M
authors: Mutoh
authors: Fumie
authors: F
authors: Hosoda
authors: Hitoshi
authors: H
authors: Tsuda
authors: Tatsuhiro
authors: T
authors: Shibata
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077547:Crizotinib; D004195:Disease Models, Animal; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D050596:Oncogene Fusion / Q000187:drug effects; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D020794:Receptor Protein-Tyrosine Kinases; C483813:Ros1 protein, mouse