1. Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies
- Author
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Chong, Stephen Jun Fei, Zhu, Fen, Dashevsky, Olga, Mizuno, Rin, Lai, Jolin X.H., Hackett, Liam, Ryan, Christine E., Collins, Mary C., Iorgulescu, J. Bryan, Guieze, Romain, Penailillo, Johany, Carrasco, Ruben, Hwang, Yeonjoo C., Munoz, Denise P., Bouhaddou, Mehdi, Lim, Yaw Chyn, Wu, Catherine J., Allan, John N., Furman, Richard R., Goh, Boon Cher, Pervaiz, Shazib, Coppe, Jean-Philippe, Mitsiades, Constantine S., and Davids, Matthew S.
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Non-Hodgkin's lymphomas ,Phosphatases ,B cells ,Proteins ,Cancer ,Apoptosis ,Health care industry - Abstract
The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques- -BH3 profiling and high-throughput kinase activity mapping--we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL- 2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression., Introduction The incorporation of the B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax into the treatment paradigm for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) has revolutionized the treatment [...]
- Published
- 2023
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