Back to Search
Start Over
A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor
- Source :
- Blood. 105:1652-1659
- Publication Year :
- 2005
- Publisher :
- American Society of Hematology, 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 :
- Pyridines
Immunology
Cell Culture Techniques
Fusion Proteins, bcr-abl
Genes, abl
Biology
Transfection
medicine.disease_cause
Philadelphia chromosome
Biochemistry
Piperazines
Cell Line
Mice
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
hemic and lymphatic diseases
medicine
Animals
Humans
Point Mutation
Protein kinase A
Protein Kinase Inhibitors
Cells, Cultured
Cell Line, Transformed
Mutation
ABL
Point mutation
Imatinib
Cell Biology
Hematology
Protein-Tyrosine Kinases
medicine.disease
Molecular biology
Protein Structure, Tertiary
Leukemia
Pyrimidines
Imatinib mesylate
Drug Resistance, Neoplasm
Benzamides
Imatinib Mesylate
Cancer research
medicine.drug
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 105
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....677dbe9982bda5e97664d2e1b346fe24