Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins.

The rapidly growing recognition of the role of oncogenic fusion proteins in the malignant transformation of multiple cancers, including lung adenocarcinoma, cholangiocarcinoma, and glioblastoma, is driving efforts to develop effective duanyu16701 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 duanyu16701 inhibitor than crizotinib (PF-02341066), an inhibitor currently in clinical evaluation for lung cancer patients harboring duanyu16701 rearrangements. Whereas crizotinib has demonstrated promising early results in patients with 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 thus necessitating identification of additional potent duanyu16701 inhibitors for therapeutic intervention. We confirm that the 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 duanyu16701 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 duanyu16701 inhibitor, and further clinical investigation to evaluate its potential therapeutic benefit for patients with malignancies is warranted.

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