title: PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease.
abstract: FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, 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-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-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 PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stover
authors.forename: Christina L
authors.initials: CL
authors.lastname: Boulton
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: Robert D
authors.initials: RD
authors.lastname: Legare
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Amaral
authors.forename: David P
authors.initials: DP
authors.lastname: Curley
authors.forename: Nicole
authors.initials: N
authors.lastname: Duclos
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rowan
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Ifor R
authors.initials: IR
authors.lastname: Williams
authors.forename: Steven E
authors.initials: SE
authors.lastname: Coutre
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D015153:Blotting, Western; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D000068877:Imatinib Mesylate; D016130:Immunophenotyping; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011233:Precipitin Tests; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D012008:Recurrence; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000166:cytology; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013997:Time Factors; D039221:mRNA Cleavage and Polyadenylation Factors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C479818:FIP1L1 protein, human; D010879:Piperazines; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; D016044:Fusion Proteins, bcr-abl; D019311:Staurosporine; C059539:midostaurin