title: Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant.
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.
authors.affiliation: Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), Universitaire Ziekenhuizen Leuven, B-3000 Leuven, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Lierman
authors.forename: Cedric
authors.initials: C
authors.lastname: Folens
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stover
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.forename: Helen
authors.initials: H
authors.lastname: Van Miegroet
authors.forename: Werner
authors.initials: W
authors.lastname: Scheers
authors.forename: Marc
authors.initials: M
authors.lastname: Boogaerts
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
mesh_terms: D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000068877:Imatinib Mesylate; D020014:K562 Cells; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology*; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D039221:mRNA Cleavage and Polyadenylation Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D001557:Benzenesulfonates; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha