Sorafenib Potently Inhibits ETV6-PDGFRβ and FLT3 Mutants, and Shows Activity Against FLT3 Mutants That Are Resistant to Other Small Molecule Inhibitors.

Abstract

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. Sorafenib also has activity against receptor tyrosine kinases from the PDGFR and VEGFR families. Here we show that sorafenib is a potent inhibitor of the ETV6-PDGFRβ tyrosine kinase that is associated with chronic myelomonocytic leukemia. Oncogenic FLT3 receptor tyrosine kinase mutants implicated in the pathogenesis of acute myeloid leukemia are also potently inhibited by sorafenib, including some of the resistant mutants that confer resistance to PKC412 and other FLT3 inhibitors. Sorafenib induced a cell cycle block and apoptosis in the AML cell lines MV4-11 and MOLM-13, both expressing FLT3 with an internal tandem duplication. In contrast, the imatinib resistant KIT(D816V) mutant that is associated with systemic mastocytosis was found to be resistant to sorafenib. These results suggest that sorafenib could be used for the treatment of myeloid leukemias expressing activated forms of PDGFRβ, FLT3, and some PKC412 resistant mutants, but not for leukemias expressing imatinib resistant KIT(D816V).