The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors.
BACKGROUND AND OBJECTIVES: Activated tyrosine kinases are implicated in the pathogenesis of chronic and acute leukemia, and represent attractive targets for therapy. Sorafenib (BAY43-9006, Nexavar) is a small molecule B-RAF inhibitor that is used for the treatment of renal cell carcinoma, and has been shown to have activity against receptor tyrosine kinases from the platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) families. We investigated the efficacy of sorafenib at inhibiting mutants of the receptor tyrosine kinases PDGFRbeta, KIT, and FLT3, which are implicated in the pathogenesis of myeloid malignancies. DESIGN AND METHODS: We tested the effect of sorafenib on the proliferation of hematopoietic cells transformed by ETV6-PDGFRbeta, FLT3 with an internal tandem duplication or D835Y point mutation, and the KIT(D816V) mutant. The direct effect of sorafenib on the activity of these kinases and their downstream signaling was tested using phospho-specific antibodies. RESULTS: We show that sorafenib is a potent inhibitor of ETV6-PDGFRbeta and FLT3 mutants, including some of the mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the acute myeloid leukemia cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication, whereas no effect was observed on four other acute myeloid leukemia cell lines. The imatinib-resistant KIT(D816V) mutant, associated with systemic mastocytosis, was found to be resistant to sorafenib. INTERPRETATION AND CONCLUSIONS: These results warrant further clinical studies of sorafenib for the treatment of myeloid malignancies expressing activated forms of PDGFRbeta and FLT3.
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tyrosine tyrosine sorafenib tyrosine sorafenib sorafenib sorafenib ETV6 PDGFRbeta FLT3 phospho FLT3 FLT3 KIT D816V PDGFRbeta FLT3 B-RAF receptor tyrosine kinases platelet-derived growth factor receptor tyrosine kinases sorafenib PDGFR vascular endothelial growth factor receptor VEGFR receptor tyrosine kinases PDGFRbeta KIT FLT3 ETV6 PDGFRbeta FLT3 Sorafenib D835Y KIT D816V kinases PDGFRbeta FLT3 imatinib sorafenib Sorafenib sorafenib BAY43-9006 Nexavar