Inhibition of Heat Shock Protein 90 Prolongs Survival of Mice with Bcr-abl-t315i-induced Leukemia and Suppresses Leukemic Stem Cells.
From: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Blood
- Publish Date: Jul 2007
- ISSN: 0006-4971
- Volume: 110
- Issue: 2
- Pages: 678-85
- Medium: Print
- Language: English
- Citation (JAMA): Peng Cong, Brain Julia, Hu Yiguo, et al. Inhibition of Heat Shock Protein 90 Prolongs Survival of Mice with Bcr-abl-t315i-induced Leukemia and Suppresses Leukemic Stem Cells.. Blood Jul 2007;110:678-85
Abstract
Development of kinase domain mutations is a major drug-resistance mechanism for tyrosine kinase inhibitors (TKIs) in cancer therapy. A particularly challenging example is found in Philadelphia chromosome-positive chronic myelogenous leukemia (CML) where all available kinase inhibitors in clinic are ineffective against the BCR-ABL mutant, T315I. As an alternative approach to kinase inhibition, an orally administered heat shock protein 90 (Hsp90) inhibitor, IPI-504, was evaluated in a murine model of CML. Treatment with IPI-504 resulted in BCR-ABL protein degradation, decreased numbers of leukemia stem cells, and prolonged survival of leukemic mice bearing the T315I mutation. Hsp90 inhibition more potently suppressed T315I-expressing leukemia clones relative to the wild-type (WT) clones in mice. Combination treatment with IPI-504 and imatinib was more effective than either treatment alone in prolonging survival of mice simultaneously bearing both WT and T315I leukemic cells. These results provide a rationale for use of an Hsp90 inhibitor as a first-line treatment in CML by inhibiting leukemia stem cells and preventing the emergence of imatinib-resistant clones in patients. Rather than inhibiting kinase activity, elimination of mutant kinases provides a new therapeutic strategy for treating BCR-ABL-induced leukemia as well as other cancers resistant to treatment with tyrosine kinase inhibitors.
Mesh Headings (Keywords): Amino Acid Substitution, Animals, Cell Line, Tumor, Enzyme Inhibitors, Fusion Proteins, bcr-abl, HSP90 Heat-Shock Proteins, Hematopoietic Stem Cells, Leukemia, Experimental, Mice, Protein-Tyrosine Kinases, Survival Analysis
Check for Full Text / PubMed Unique Identifier (PMID): 17395781
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