Cancer Cell
Volume 3, Issue 5, May 2003, Pages 459-469
Journal home page for Cancer Cell

Article
PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease

https://doi.org/10.1016/S1535-6108(03)00108-9Get rights and content
Under an Elsevier user license
open archive

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.

Cited by (0)

10

These authors contributed equally to this work.