Abstract
The FIP1L1-PDGFRA oncogene is a common cause of chronic eosinophilic leukemia (CEL), and encodes an activated tyrosine kinase that is inhibited by imatinib. FIP1L1-PDGFRA-positive patients with CEL respond to low-dose imatinib therapy, but resistance due to acquired T674I mutation has been observed. We report here the identification of sorafenib as a potent inhibitor of the FIP1 like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRalpha) (T674I) mutant. Sorafenib inhibited the proliferation of FIP1L1-PDGFRalpha and FIP1L1-PDGFRalpha(T674I)-transformed Ba/F3 cells and induced apoptosis of the EOL-1 cell line at a low nanomolar concentration. Western blot analysis confirmed that these effects were due to a direct effect on FIP1L1-PDGFRalpha and FIP1L1-PDGFRalpha(T674I). Sorafenib was recently approved for the treatment of renal cell carcinoma. Our data suggest that low doses of sorafenib could be efficient for the treatment of FIP1L1-PDGFRA-positive CEL and could be used to overcome resistance to imatinib associated with the T674I mutation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Benzamides
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Benzenesulfonates / pharmacology*
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Benzenesulfonates / therapeutic use
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Carcinoma / drug therapy
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Carcinoma / genetics
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Carcinoma / metabolism
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Cell Proliferation / drug effects
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Drug Evaluation, Preclinical
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Humans
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Hypereosinophilic Syndrome / drug therapy
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Hypereosinophilic Syndrome / genetics
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Hypereosinophilic Syndrome / metabolism*
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Imatinib Mesylate
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K562 Cells
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Kidney Neoplasms / drug therapy
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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Mutation
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Niacinamide / analogs & derivatives
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Oncogene Proteins, Fusion / antagonists & inhibitors*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Phenylurea Compounds
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Piperazines / pharmacology*
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Point Mutation*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Pyridines / pharmacology*
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Pyridines / therapeutic use
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Pyrimidines / pharmacology*
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Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors*
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Receptor, Platelet-Derived Growth Factor alpha / genetics
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Receptor, Platelet-Derived Growth Factor alpha / metabolism
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Sorafenib
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mRNA Cleavage and Polyadenylation Factors / antagonists & inhibitors*
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mRNA Cleavage and Polyadenylation Factors / genetics
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mRNA Cleavage and Polyadenylation Factors / metabolism
Substances
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Benzamides
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Benzenesulfonates
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Oncogene Proteins, Fusion
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Phenylurea Compounds
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Piperazines
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Protein Kinase Inhibitors
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Pyridines
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Pyrimidines
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mRNA Cleavage and Polyadenylation Factors
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Niacinamide
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Imatinib Mesylate
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Sorafenib
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FIP1L1-PDGFRA fusion protein, human
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Receptor, Platelet-Derived Growth Factor alpha