| Literature DB >> 31543463 |
Romain Guièze1, Vivian M Liu2, Daniel Rosebrock3, Alexis A Jourdain4, María Hernández-Sánchez5, Aina Martinez Zurita3, Jing Sun6, Elisa Ten Hacken7, Kaitlyn Baranowski8, Philip A Thompson9, Jin-Mi Heo10, Zachary Cartun8, Ozan Aygün3, J Bryan Iorgulescu11, Wandi Zhang8, Giulia Notarangelo2, Dimitri Livitz3, Shuqiang Li3, Matthew S Davids12, Anat Biran8, Stacey M Fernandes8, Jennifer R Brown13, Ana Lako14, Zoe B Ciantra14, Matthew A Lawlor15, Derin B Keskin7, Namrata D Udeshi3, William G Wierda9, Kenneth J Livak8, Anthony G Letai12, Donna Neuberg16, J Wade Harper10, Steven A Carr3, Federica Piccioni3, Christopher J Ott15, Ignaty Leshchiner3, Cory M Johannessen3, John Doench3, Vamsi K Mootha4, Gad Getz17, Catherine J Wu18.
Abstract
Mitochondrial 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.Entities:
Keywords: AMPK; BCL-2; CRISPR/Cas9; chronic lymphocytic leukemia; clonal evolution; drug resistance; genome-wide screen; metabolism; mitochondrion; venetoclax
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Year: 2019 PMID： 31543463 PMCID： PMC6801112 DOI： 10.1016/j.ccell.2019.08.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743