Author/Authors :
Cools، نويسنده , , Jan and Stover، نويسنده , , Elizabeth H and Boulton، نويسنده , , Christina L and Gotlib، نويسنده , , Jason and Legare، نويسنده , , Robert D and Amaral، نويسنده , , Sonia M and Curley، نويسنده , , David P and Duclos، نويسنده , , Nicole and Rowan، نويسنده , , Rebecca and Kutok، نويسنده , , Jeffery L and Lee، نويسنده , , Benjamin H and Williams، نويسنده , , Ifor R and Coutre، نويسنده , , Steven E and Stone، نويسنده , , Richard M and DeAngelo، نويسنده , , Daniel J and Marynen، نويسنده , , Peter J. Manley، نويسنده , , Paul W and Meyer، نويسنده , , Thomas and Fabbro، نويسنده , , Doriano and Neuberg، نويسنده , , Donna and Weisberg، نويسنده , , Ellen and Griffin، نويسنده , , James R. and Gilliland، نويسنده , , D.Gary، نويسنده ,
Abstract :
FIP1L1-PDGFRα causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRα, PDGFRβ, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRα, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRα-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRα, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRα-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRα and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.
