Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins

Monika A. Davare, Anna Saborowski, Christopher A. Eide, Cristina Tognon, Rebecca L. Smith, Johannes Elferich, Anupriya Agarwal, Jeffrey W. Tyner, Ujwal P. Shinde, Scott W. Lowe, Brian J. Druker

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)19519-19524
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number48
StatePublished - Nov 26 2013

ASJC Scopus subject areas

  • General


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