Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study
| Autor: | Sandra W. Cowan-Jacob, James D. Griffin, Jürgen Mestan, Arghya Ray, Paul W. Manley |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Protein Conformation Immunology Mutant Fusion Proteins bcr-abl Mutagenesis (molecular biology technique) Antineoplastic Agents Biology medicine.disease_cause Biochemistry Mice Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Animals Humans Point Mutation neoplasms Mutation ABL Point mutation Imatinib Cell Biology Hematology Molecular biology Protein Structure Tertiary Pyrimidines Imatinib mesylate Nilotinib Drug Resistance Neoplasm Mutagenesis Cancer research medicine.drug |
| Zdroj: | Blood. 109:5011-5015 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2006-01-015347 |
| Popis: | Patients with advanced stages of chronic myeloid leukemia (CML) often manifest imatinib mesylate resistance associated with point mutations in BCR-ABL. AMN107 is a new higher-potency inhibitor of BCR-ABL. To identify mutations in BCR-ABL that could result in resistance to AMN107, a cDNA library of BCR-ABL mutants was introduced into Ba/F3 cells followed by selection in AMN107 (0.125-0.5 μM). A total of 86 individual, drug-resistant colonies were recovered, and the SH3, SH2, and kinase domains of BCR-ABL were sequenced. A total of 46 colonies had single point mutations in BCR-ABL, with a total of 17 different mutations, all within the kinase domain. The other 40 colonies had multiple point mutations and were not analyzed further. Each of the 17 single point mutants were reconstructed by site-directed mutagenesis of native BCR-ABL and found to be approximately 2.5- to 800-fold more resistant to AMN107 than native BCR-ABL. The mutations included 6 known imatinib mesylate–resistant mutations, including T315I, which showed complete resistance to AMN107. Interestingly, most AMN107-resistant mutants were also resistant to imatinib mesylate. These results may predict some of the resistance mutations that will be detected in clinical trials with this kinase inhibitor. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|