Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins Journal Article


Authors: Davare, M. A.; Saborowski, A.; Eide, C. A.; Tognon, C.; Smith, R. L.; Elferich, J.; Agarwal, A.; Tyner, J. W.; Shinde, U. P.; Lowe, S. W.; Druker, B. J.
Article Title: Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins
Abstract: The rapidly growing recognition of the role of oncogenic ROS1 fusion proteins in the malignant transformation of multiple cancers, including lung adenocarcinoma, cholangiocarcinoma, and glioblastoma, is driving efforts to develop effective ROS1 inhibitors for use as molecularly targeted therapy. Using a multidisciplinary approach involving small molecule screening in combination with in vitro and in vivo tumor models, we show that foretinib (GSK1363089) is a more potent ROS1 inhibitor than crizotinib (PF-02341066), an ALK/ ROS inhibitor currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Whereas crizotinib has demonstrated promising early results in patients with ROS1-rearranged non-small-cell lung carcinoma, recently emerging clinical evidence suggests that patients may develop crizotinib resistance due to acquired point mutations in the kinase domain of ROS1, thus necessitating identification of additional potent ROS1 inhibitors for therapeutic intervention. We confirm that the ROS1G2032R mutant, recently reported in clinical resistance to crizotinib, retains foretinib sensitivity at concentrations below safe, clinically achievable levels. Furthermore, we use an accelerated mutagenesis screen to preemptively identify mutations in the ROS1 kinase domain that confer resistance to crizotinib and demonstrate that these mutants also remain foretinib sensitive. Taken together, our data strongly suggest that foretinib is a highly effective ROS1 inhibitor, and further clinical investigation to evaluate its potential therapeutic benefit for patients with ROS1-driven malignancies is warranted.
Keywords: controlled study; unclassified drug; nonhuman; cancer patient; animal cell; mouse; lung non small cell cancer; in vivo study; in vitro study; hybrid protein; point mutation; mutagenesis; crizotinib; foretinib; priority journal; article; ros1 fusion protein
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 110
Issue: 48
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2013-11-26
Start Page: 19519
End Page: 19524
Language: English
DOI: 10.1073/pnas.1319583110
PROVIDER: scopus
PMCID: PMC3845150
PUBMED: 24218589
DOI/URL:
Notes: Export Date: 2 January 2014 -- CODEN: PNASA -- Source: Scopus
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  1. Scott W Lowe
    249 Lowe