Mouse Model for ROS1-Rearranged Lung Cancer

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

研究成果: Article査読

48 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号e56010
ジャーナルPloS one
8
2
DOI
出版ステータスPublished - 2013 2月 13
外部発表はい

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)
  • 農業および生物科学(全般)
  • 一般

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