Back to Search
Start Over
PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease
- Source :
- Cancer cell. 3(5)
- Publication Year :
- 2003
-
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. ispartof: Cancer cell vol:3 issue:5 pages:459-69 ispartof: location:United States status: published
- Subjects :
- Cancer Research
Receptor, Platelet-Derived Growth Factor alpha
Time Factors
Research Support, U.S. Gov't, P.H.S
Drug Resistance
Fusion Proteins, bcr-abl
Tyrosine-kinase inhibitor
Piperazines
Mice
0302 clinical medicine
Bone Marrow
Recurrence
hemic and lymphatic diseases
Bone Marrow Transplantation
0303 health sciences
ABL
Hypereosinophilic syndrome
Research Support, Non-U.S. Gov't
3. Good health
Oncology
030220 oncology & carcinogenesis
Benzamides
Imatinib Mesylate
Tyrosine kinase
medicine.drug
medicine.drug_class
Blotting, Western
Genetic Vectors
Antineoplastic Agents
Cell Line
Immunophenotyping
03 medical and health sciences
Myeloproliferative Disorders
medicine
Animals
Humans
neoplasms
030304 developmental biology
mRNA Cleavage and Polyadenylation Factors
Chronic eosinophilic leukemia
Dose-Response Relationship, Drug
Models, Genetic
business.industry
Imatinib
Cell Biology
medicine.disease
Staurosporine
Precipitin Tests
Disease Models, Animal
Imatinib mesylate
Pyrimidines
Retroviridae
Immunology
Mutation
Cancer research
business
Spleen
Subjects
Details
- ISSN :
- 15356108
- Volume :
- 3
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Cancer cell
- Accession number :
- edsair.doi.dedup.....6ba0ed3b0728acf4575087575e27ffbd