Cargando…
Identification of Drug Combinations Containing Imatinib for Treatment of BCR-ABL+ Leukemias
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...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100887/ https://www.ncbi.nlm.nih.gov/pubmed/25029499 http://dx.doi.org/10.1371/journal.pone.0102221 |
_version_ | 1782326734381645824 |
---|---|
author | Kang, Yunyi Hodges, Andrew Ong, Edison Roberts, William Piermarocchi, Carlo Paternostro, Giovanni |
author_facet | Kang, Yunyi Hodges, Andrew Ong, Edison Roberts, William Piermarocchi, Carlo Paternostro, Giovanni |
author_sort | Kang, Yunyi |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4100887 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41008872014-07-18 Identification of Drug Combinations Containing Imatinib for Treatment of BCR-ABL+ Leukemias Kang, Yunyi Hodges, Andrew Ong, Edison Roberts, William Piermarocchi, Carlo Paternostro, Giovanni PLoS One Research Article 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. Public Library of Science 2014-07-16 /pmc/articles/PMC4100887/ /pubmed/25029499 http://dx.doi.org/10.1371/journal.pone.0102221 Text en © 2014 Kang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kang, Yunyi Hodges, Andrew Ong, Edison Roberts, William Piermarocchi, Carlo Paternostro, Giovanni Identification of Drug Combinations Containing Imatinib for Treatment of BCR-ABL+ Leukemias |
title | Identification of Drug Combinations Containing Imatinib for Treatment of BCR-ABL+ Leukemias |
title_full | Identification of Drug Combinations Containing Imatinib for Treatment of BCR-ABL+ Leukemias |
title_fullStr | Identification of Drug Combinations Containing Imatinib for Treatment of BCR-ABL+ Leukemias |
title_full_unstemmed | Identification of Drug Combinations Containing Imatinib for Treatment of BCR-ABL+ Leukemias |
title_short | Identification of Drug Combinations Containing Imatinib for Treatment of BCR-ABL+ Leukemias |
title_sort | identification of drug combinations containing imatinib for treatment of bcr-abl+ leukemias |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100887/ https://www.ncbi.nlm.nih.gov/pubmed/25029499 http://dx.doi.org/10.1371/journal.pone.0102221 |
work_keys_str_mv | AT kangyunyi identificationofdrugcombinationscontainingimatinibfortreatmentofbcrablleukemias AT hodgesandrew identificationofdrugcombinationscontainingimatinibfortreatmentofbcrablleukemias AT ongedison identificationofdrugcombinationscontainingimatinibfortreatmentofbcrablleukemias AT robertswilliam identificationofdrugcombinationscontainingimatinibfortreatmentofbcrablleukemias AT piermarocchicarlo identificationofdrugcombinationscontainingimatinibfortreatmentofbcrablleukemias AT paternostrogiovanni identificationofdrugcombinationscontainingimatinibfortreatmentofbcrablleukemias |