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The ability of sorafenib to inhibit oncogenic PDGFRß and FLT3 mutants and overcome resistance to other small molecule inhibitors

From the Department of Molecular and Developmental Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Leuven, Leuven, Belgium (EL, IL, HVM, NM, PM, JC); Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain (IL)

Correspondence: Jan Cools, M.D., Department of Molecular and Developmental Genetics, Campus Gasthuisberg O&N1, Herestraat 49 (BOX 602), B-3000 Leuven, Belgium. E-mail: jan.cools{at}med.kuleuven.be

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 PDGFRß, 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-PDGFRß, 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-PDGFRß 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 PDGFRß and FLT3.

Key words: oncogene, tyrosine kinase, resistance.

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