4.6 Article

Mouse Model for ROS1-Rearranged Lung Cancer

Journal

PLOS ONE
Volume 8, Issue 2, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0056010

Keywords

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Funding

  1. Program for Promotion of Fundamental Studies in Health Sciences from the National Institute of Biomedical Innovation, National Cancer Center Research and Development Fund [23-A-7, 23-B-28]
  2. Research Grant of the Princess Takamatsu Cancer Research Fund
  3. Ministry of Health, Labour and Welfare for the 3rd-term Comprehensive 10-year Strategy for Cancer Control
  4. National Cancer Center Research and Development Fund, Japan

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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.

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