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Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia

Although the BTK inhibitor ibrutinib has transformed the management of patients with CLL, it does not induce substantial apoptosis in vitro, and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, a...

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Autores principales: Deng, Jing, Isik, Elif, Fernandes, Stacey M., Brown, Jennifer R., Letai, Anthony, Davids, Matthew S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555835/
https://www.ncbi.nlm.nih.gov/pubmed/28111464
http://dx.doi.org/10.1038/leu.2017.32
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author Deng, Jing
Isik, Elif
Fernandes, Stacey M.
Brown, Jennifer R.
Letai, Anthony
Davids, Matthew S.
author_facet Deng, Jing
Isik, Elif
Fernandes, Stacey M.
Brown, Jennifer R.
Letai, Anthony
Davids, Matthew S.
author_sort Deng, Jing
collection PubMed
description Although the BTK inhibitor ibrutinib has transformed the management of patients with CLL, it does not induce substantial apoptosis in vitro, and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib. We studied CLL patient samples treated ex vivo with both drugs, as well as primary samples from CLL patients on clinical trials of both drugs. We found that BTK inhibition enhances mitochondrial BCL-2 dependence without significantly altering overall mitochondrial priming. Enhancement of BCL-2 dependence was accompanied by an increase in the pro-apoptotic protein BIM. In contrast, treatment with the selective BCL-2 inhibitor venetoclax enhanced overall mitochondrial priming without increasing BCL-2 dependence. Pre-treatment of CLL cells with either BTK inhibitor, whether ex vivo or in vivo in patients, enhanced killing by venetoclax. Our data suggest that BTK inhibition enhances mitochondrial BCL2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition.
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spelling pubmed-55558352017-08-15 Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia Deng, Jing Isik, Elif Fernandes, Stacey M. Brown, Jennifer R. Letai, Anthony Davids, Matthew S. Leukemia Article Although the BTK inhibitor ibrutinib has transformed the management of patients with CLL, it does not induce substantial apoptosis in vitro, and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib. We studied CLL patient samples treated ex vivo with both drugs, as well as primary samples from CLL patients on clinical trials of both drugs. We found that BTK inhibition enhances mitochondrial BCL-2 dependence without significantly altering overall mitochondrial priming. Enhancement of BCL-2 dependence was accompanied by an increase in the pro-apoptotic protein BIM. In contrast, treatment with the selective BCL-2 inhibitor venetoclax enhanced overall mitochondrial priming without increasing BCL-2 dependence. Pre-treatment of CLL cells with either BTK inhibitor, whether ex vivo or in vivo in patients, enhanced killing by venetoclax. Our data suggest that BTK inhibition enhances mitochondrial BCL2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition. 2017-01-23 2017-10 /pmc/articles/PMC5555835/ /pubmed/28111464 http://dx.doi.org/10.1038/leu.2017.32 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Deng, Jing
Isik, Elif
Fernandes, Stacey M.
Brown, Jennifer R.
Letai, Anthony
Davids, Matthew S.
Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia
title Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia
title_full Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia
title_fullStr Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia
title_full_unstemmed Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia
title_short Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia
title_sort bruton’s tyrosine kinase inhibition increases bcl-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555835/
https://www.ncbi.nlm.nih.gov/pubmed/28111464
http://dx.doi.org/10.1038/leu.2017.32
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