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Targeting MCL-1/BCL-X(L) Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia

ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199...

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Autores principales: Lin, Kevin H., Winter, Peter S., Xie, Abigail, Roth, Cullen, Martz, Colin A., Stein, Elizabeth M., Anderson, Gray R., Tingley, Jennifer P., Wood, Kris C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901329/
https://www.ncbi.nlm.nih.gov/pubmed/27283158
http://dx.doi.org/10.1038/srep27696
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author Lin, Kevin H.
Winter, Peter S.
Xie, Abigail
Roth, Cullen
Martz, Colin A.
Stein, Elizabeth M.
Anderson, Gray R.
Tingley, Jennifer P.
Wood, Kris C.
author_facet Lin, Kevin H.
Winter, Peter S.
Xie, Abigail
Roth, Cullen
Martz, Colin A.
Stein, Elizabeth M.
Anderson, Gray R.
Tingley, Jennifer P.
Wood, Kris C.
author_sort Lin, Kevin H.
collection PubMed
description ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-X(L) as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-X(L). By targeting MCL-1 and BCL-X(L), resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-X(L) alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-X(L) and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.
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spelling pubmed-49013292016-06-13 Targeting MCL-1/BCL-X(L) Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia Lin, Kevin H. Winter, Peter S. Xie, Abigail Roth, Cullen Martz, Colin A. Stein, Elizabeth M. Anderson, Gray R. Tingley, Jennifer P. Wood, Kris C. Sci Rep Article ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-X(L) as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-X(L). By targeting MCL-1 and BCL-X(L), resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-X(L) alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-X(L) and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199. Nature Publishing Group 2016-06-10 /pmc/articles/PMC4901329/ /pubmed/27283158 http://dx.doi.org/10.1038/srep27696 Text en Copyright © 2016, Macmillan Publishers Limited https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/)
spellingShingle Article
Lin, Kevin H.
Winter, Peter S.
Xie, Abigail
Roth, Cullen
Martz, Colin A.
Stein, Elizabeth M.
Anderson, Gray R.
Tingley, Jennifer P.
Wood, Kris C.
Targeting MCL-1/BCL-X(L) Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia
title Targeting MCL-1/BCL-X(L) Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia
title_full Targeting MCL-1/BCL-X(L) Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia
title_fullStr Targeting MCL-1/BCL-X(L) Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia
title_full_unstemmed Targeting MCL-1/BCL-X(L) Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia
title_short Targeting MCL-1/BCL-X(L) Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia
title_sort targeting mcl-1/bcl-x(l) forestalls the acquisition of resistance to abt-199 in acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901329/
https://www.ncbi.nlm.nih.gov/pubmed/27283158
http://dx.doi.org/10.1038/srep27696
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