PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease.
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.
Cools
Jan
J
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Stover
Elizabeth H
EH
Boulton
Christina L
CL
Gotlib
Jason
J
Legare
Robert D
RD
Amaral
Sonia M
SM
Curley
David P
DP
Duclos
Nicole
N
Rowan
Rebecca
R
Kutok
Jeffery L
JL
Lee
Benjamin H
BH
Williams
Ifor R
IR
Coutre
Steven E
SE
Stone
Richard M
RM
DeAngelo
Daniel J
DJ
Marynen
Peter
P
Manley
Paul W
PW
Meyer
Thomas
T
Fabbro
Doriano
D
Neuberg
Donna
D
Weisberg
Ellen
E
Griffin
James D
JD
Gilliland
D Gary
DG
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*
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