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Chronic lymphocytic leukemia

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

Leukemia volume 31, pages 2075–2084 (2017)Cite this article

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Abstract

Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (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 BCL-2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition.

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Acknowledgements

We thank the patients who generously donated their samples for this study; John F Daley II and Suzan Lazo-Kallanian for technical support with flow cytometry; Abbvie for providing venetoclax, and Acerta for providing acalabrutinib. This work was funded by the National Institutes of Health (R01CA129974) and a Dana-Farber Gloria Spivak Faculty Advancement Award. MSD is an American Society of Clinical Oncology Career Development Award recipient and a recipient of a National Institutes of Health Loan Repayment Program award.

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  1. A Letai and M S Davids: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    J Deng, E Isik, S M Fernandes, J R Brown, A Letai & M S Davids

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  1. J Deng
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  2. E Isik
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  3. S M Fernandes
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  4. J R Brown
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  5. A Letai
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Correspondence to A Letai or M S Davids.

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Competing interests

JD, EI and SMF have no relevant conflicts of interest. JRB has received consulting fees from Abbvie, Genentech, Pharmacyclics and Janssen. AL is a paid advisor to and his laboratory receives research sponsorship from AbbVie, Astra-Zeneca and Tetralogic. MSD has received research sponsorship from Pharmacyclics and Genentech, and has received consulting fees from Genentech, Abbvie, Pharmacyclics and Janssen.

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Deng, J., Isik, E., Fernandes, S. et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 31, 2075–2084 (2017). https://doi.org/10.1038/leu.2017.32

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