Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins
Abstract
ROS1 fusion kinases are critical oncogenes in several malignancies, suggesting that ROS1 inhibitors are likely to be effective molecularly targeted therapies in these patients. Although phase I/II clinical trials using the ALK/ROS1 inhibitor crizotinib to treat ROS1 fusion-harboring non-small-cell lung cancer patients demonstrate early success, evidence of clinical resistance to crizotinib due to the acquired ROS1G2032R mutation was recently reported. Here, we demonstrate that foretinib is a more potent ROS1 inhibitor than crizotinib in vitro and in vivo and remains effective against crizotinib-resistant ROS1 kinase domain mutations, including ROS1 G2032R. Taken together, our findings establish foretinib as a highly promising therapeutic candidate for treating patients with ROS1-driven malignancies and provide rationale for rapid clinical translation.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- November 2013
- DOI:
- 10.1073/pnas.1319583110
- Bibcode:
- 2013PNAS..11019519D