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A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor.
- Source :
-
Blood [Blood] 2005 Feb 15; Vol. 105 (4), pp. 1652-9. Date of Electronic Publication: 2004 Sep 30. - Publication Year :
- 2005
-
Abstract
- In Philadelphia-positive (Ph(+)) leukemia, point mutations within the Bcr-Abl kinase domain emerged as a major mechanism of resistance to imatinib mesylate. We established a cell-based screening strategy for detection of clinically relevant point mutations using Bcr-Abl-transformed Ba/F3 cells. We identified 32 different single-point mutations within the kinase domain of Bcr-Abl. The pattern and frequency of mutations in this cell culture-based screen resembled the pattern and frequency observed in resistant patients. We then applied this screen to an alternative Abl kinase inhibitor. Using PD166326, the frequency of resistant colonies emerging at 5 to 10 times the median growth inhibition (IC50) of PD166326 was significantly lower than with imatinib. In addition, PD166326 produced a distinct pattern of Bcr-Abl mutations. The majority of mutations that came up with both imatinib and PD166326 could effectively be suppressed by increasing the dose of PD166326 to 50 to 500 nM. In contrast, only a few mutations could be suppressed by increasing the imatinib dose to 5 to 10 microM. However, 3 mutations affecting F317 displayed complete resistance to PD166326, but could be effectively inhibited by standard concentrations of imatinib. Thus, this robust and simple screening system provides a rational basis for combinatorial and sequential treatment strategies in targeted cancer therapy.
- Subjects :
- Animals
Benzamides
Cell Culture Techniques methods
Cell Line
Cell Line, Transformed
Cells, Cultured
Fusion Proteins, bcr-abl biosynthesis
Fusion Proteins, bcr-abl genetics
Humans
Imatinib Mesylate
Leukemia, Myelogenous, Chronic, BCR-ABL Positive enzymology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
Mice
Piperazines pharmacology
Protein Structure, Tertiary drug effects
Protein Structure, Tertiary genetics
Protein-Tyrosine Kinases biosynthesis
Protein-Tyrosine Kinases genetics
Transfection
Drug Resistance, Neoplasm genetics
Fusion Proteins, bcr-abl antagonists & inhibitors
Genes, abl drug effects
Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy
Point Mutation
Protein Kinase Inhibitors pharmacology
Protein-Tyrosine Kinases antagonists & inhibitors
Pyridines pharmacology
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 105
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 15459011
- Full Text :
- https://doi.org/10.1182/blood-2004-06-2445