1. Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies.
- Author
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Chong, Stephen, Zhu, Fen, Dashevsky, Olga, Mizuno, Rin, Lai, Jolin, Hackett, Liam, Ryan, Christine, Collins, Mary, Iorgulescu, J, Guièze, Romain, Penailillo, Johany, Carrasco, Ruben, Hwang, Yeonjoo, Muñoz, Denise, Lim, Yaw, Wu, Catherine, Allan, John, Furman, Richard, Goh, Boon, Pervaiz, Shazib, Coppé, Jean-Philippe, Mitsiades, Constantine, Davids, Matthew, and Bouhaddou, Mehdi
- Subjects
Apoptosis survival pathways ,Hematology ,Oncology ,Phosphoprotein phosphatases ,Protein kinases ,Mice ,Animals ,Humans ,Leukemia ,Lymphocytic ,Chronic ,B-Cell ,Drug Resistance ,Neoplasm ,Proto-Oncogene Proteins c-bcl-2 ,Bridged Bicyclo Compounds ,Heterocyclic ,bcl-X Protein ,Apoptosis Regulatory Proteins ,Lymphoma ,Large B-Cell ,Diffuse ,Cell Line ,Tumor ,Antineoplastic Agents ,Apoptosis ,Myeloid Cell Leukemia Sequence 1 Protein - 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.
- Published
- 2023