FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies
| Autor: | Nicole Duclos, Jeffery L. Kutok, Constantine S. Mitsiades, Allison Coburn, Jennifer Adelsperger, D. G. Gilliland, Rachel Okabe, Brian J. P. Huntly, James D. Griffin, Ifor R. Williams, Benjamin H. Lee, Sandra A. Moore, Jing Chen, Kenneth C. Anderson, Sarah Cohen, Doriano Fabbro |
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| Rok vydání: | 2005 |
| Předmět: |
musculoskeletal diseases
Cancer Research Lymphoma B-Cell Thanatophoric Dysplasia medicine.drug_class Recombinant Fusion Proteins medicine.medical_treatment Biology Transfection Receptor tyrosine kinase Tyrosine-kinase inhibitor Targeted therapy Mice Myeloproliferative Disorders Cell Line Tumor Genetics medicine Animals Receptor Fibroblast Growth Factor Type 3 Molecular Biology Multiple myeloma Bone Marrow Transplantation Protein-Tyrosine Kinases Fibroblast growth factor receptor 3 Staurosporine medicine.disease Growth Inhibitors Lymphoma Disease Models Animal stomatognathic diseases medicine.anatomical_structure Hematologic Neoplasms Immunology Cancer research biology.protein Bone marrow Multiple Myeloma |
| Zdroj: | Oncogene. 24:8259-8267 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1208989 |
| Popis: | Reccurent chromosomal translocation t(4;14) (p16.3;q32.3) occurs in patients with multiple myeloma (MM) and is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3) that sometimes may contain the activation mutations such as K650E thanatophoric dysplasia type II (TDII). Although there have been significant advances in therapy for MM including the use of proteasome inhibitors, t(4;14) MM has a particularly poor prognosis and most patients still die from complications related to their disease or therapy. One potential therapeutic strategy is to inhibit FGFR3 in those myeloma patients that overexpress the receptor tyrosine kinase due to chromosomal translocation. Here we evaluated PKC412, a small molecule tyrosine kinase inhibitor, for treatment of FGFR3-induced hematopoietic malignancies. PKC412 inhibited kinase activation and proliferation of hematopoietic Ba/F3 cells transformed by FGFR3 TDII or a TEL-FGFR3 fusion. Similar results were obtained in PKC412 inhibition of several different t(4;14)-positive human MM cell lines. Furthermore, treatment with PKC412 resulted in a statistically significant prolongation of survival in murine bone marrow transplant models of FGFR3 TDII-induced pre-B cell lymphoma, or a peripheral T-cell lymphoma associated TEL-FGFR3 fusion-induced myeloproliferative disease. These data indicate that PKC412 may be a useful molecularly targeted therapy for MM associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants. |
| Databáze: | OpenAIRE |
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