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Mouse Model for ROS1-Rearranged Lung Cancer

2013; Public Library of Science; Volume: 8; Issue: 2 Linguagem: Inglês

10.1371/journal.pone.0056010

1932-6203

Yasuhito Arai, Yasushi Totoki, Hiroyuki Takahashi, Hiromi Nakamura, Natsuko Hama, Takashi Kohno, Koji Tsuta, Akihiko Yoshida, Hisao Asamura, Michihiro Mutoh, Fumie Hosoda, Hitoshi Tsuda, Tatsuhiro Shibata,

Cancer-related gene regulation

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.