학술논문
Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies.
Document Type
article
Author
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; Bouhaddou, Mehdi
Source
Journal of Clinical Investigation. 133(22)
Subject
Language
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.