Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies

Publication date: Available online 19 September 2019Source: Cancer CellAuthor(s): Romain Guièze, Vivian M. Liu, Daniel Rosebrock, Alexis A. Jourdain, María Hernández-Sánchez, Aina Martinez Zurita, Jing Sun, Elisa Ten Hacken, Kaitlyn Baranowski, Philip A. Thompson, Jin-Mi Heo, Zachary Cartun, Ozan Aygün, J. Bryan Iorgulescu, Wandi Zhang, Giulia Notarangelo, Dimitri Livitz, Shuqiang Li, Matthew S. Davids, Anat BiranSummaryMitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research

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