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Title: Sorafenib is a potent inhibitor of FIP1L1-PDGFRalpha and the imatinib-resistant FIP1L1-PDGFRalpha T674I mutant
Authors: Lierman, Els
Folens, Cedric
Stover, Elizabeth H
Mentens, Nicole
Van Miegroet, Helen
Scheers, Werner
Boogaerts, Marc
Vandenberghe, Peter
Marynen, Peter
Cools, Jan # ×
Issue Date: Aug-2006
Publisher: W.B. Saunders
Series Title: Blood vol:108 issue:4 pages:1374-1376
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.
URI: 
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Department of Human Genetics - miscellaneous
Hematology Section (-)
Clinical Genetics Section (-)
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

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