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Identification of drug combinations containing imatinib for treatment of BCR-ABL+ leukemias
- Source :
- PLoS ONE, Vol 9, Iss 7, p e102221 (2014), PLoS ONE
- Publication Year :
- 2014
- Publisher :
- Public Library of Science (PLoS), 2014.
-
Abstract
- The BCR-ABL translocation is found in chronic myeloid leukemia (CML) and in Ph+ acute lymphoblastic leukemia (ALL) patients. Although imatinib and its analogues have been used as front-line therapy to target this mutation and control the disease for over a decade, resistance to the therapy is still observed and most patients are not cured but need to continue the therapy indefinitely. It is therefore of great importance to find new therapies, possibly as drug combinations, which can overcome drug resistance. In this study, we identified eleven candidate anti-leukemic drugs that might be combined with imatinib, using three approaches: a kinase inhibitor library screen, a gene expression correlation analysis, and literature analysis. We then used an experimental search algorithm to efficiently explore the large space of possible drug and dose combinations and identified drug combinations that selectively kill a BCR-ABL+ leukemic cell line (K562) over a normal fibroblast cell line (IMR-90). Only six iterations of the algorithm were needed to identify very selective drug combinations. The efficacy of the top forty-nine combinations was further confirmed using Ph+ and Ph- ALL patient cells, including imatinib-resistant cells. Collectively, the drug combinations and methods we describe might be a first step towards more effective interventions for leukemia patients, especially those with the BCR-ABL translocation.
- Subjects :
- Drug
media_common.quotation_subject
Fusion Proteins, bcr-abl
lcsh:Medicine
Antineoplastic Agents
Drug resistance
Pharmacology
Piperazines
Hematologic Cancers and Related Disorders
Cell Line, Tumor
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
hemic and lymphatic diseases
Antineoplastic Combined Chemotherapy Protocols
Drug Discovery
Leukemias
medicine
Medicine and Health Sciences
Humans
lcsh:Science
media_common
Multidisciplinary
Dose-Response Relationship, Drug
Drug discovery
business.industry
lcsh:R
Myeloid leukemia
Imatinib
Hematology
medicine.disease
3. Good health
Leukemia
Imatinib mesylate
Pyrimidines
Oncology
Drug Resistance, Neoplasm
Benzamides
Imatinib Mesylate
lcsh:Q
business
Algorithms
medicine.drug
K562 cells
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 9
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....76a137c62acd361add0e9e03e5e9e9ae