Lierman E, Folens C, Stover EH, Mentens N, Van Miegroet H, Scheers W, Boogaerts M, Vandenberghe P, Marynen P, Cools J
Sorafenib (BAY43-9006) is a potent inhibitor of FIP1L1-PDGFR{alpha} and the imatinib resistant FIP1L1-PDGFR{alpha} T674I mutant. [JOURNAL ARTICLE]
Blood 2006 Apr 27.
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 CEL patients 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 low nanomolar concentration. Western blot analysis confirmed that these effects were due to a direct effect on FIP1L1-PDGFRalpha and FIP1L1-PDGFRalpha (T674I). Sorafenib (BAY43-9006, Nexavar(R) ) 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.
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