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

Romain Guièze(Broad Institute), Vivian M. Liu(Harvard University), Daniel Rosebrock(Broad Institute), Alexis A. Jourdain(Broad Institute), María Hernández‐Sánchez(Universidad de Salamanca), Aina Zurita Martinez(Broad Institute), Jing Sun(Broad Institute), Elisa ten Hacken(Broad Institute), Kaitlyn Baranowski(Dana-Farber Cancer Institute), Philip A. Thompson(The University of Texas MD Anderson Cancer Center), Jin-Mi Heo(Harvard University), Zachary Cartun(Dana-Farber Cancer Institute), Ozan Aygün(Broad Institute), J. Bryan Iorgulescu(Brigham and Women's Hospital), Wandi Zhang(Dana-Farber Cancer Institute), Giulia Notarangelo(Harvard University), Dimitri Livitz(Broad Institute), Shuqiang Li(Broad Institute), Matthew S. Davids(Brigham and Women's Hospital), Anat Biran(Dana-Farber Cancer Institute), Stacey M. Fernandes(Dana-Farber Cancer Institute), Jennifer R. Brown(Broad Institute), Ana Lako(Dana-Farber Cancer Institute), Zoe Ciantra(Dana-Farber Cancer Institute), Matthew A. Lawlor(Harvard University), Derin B. Keskin(Broad Institute), Namrata D. Udeshi(Broad Institute), William G. Wierda(The University of Texas MD Anderson Cancer Center), Kenneth J. Livak(Dana-Farber Cancer Institute), Anthony Letai(Brigham and Women's Hospital), Donna Neuberg(Harvard University), J. Wade Harper(Harvard University), Steven A. Carr(Broad Institute), Federica Piccioni(Broad Institute), Christopher J. Ott(Harvard University), Ignaty Leshchiner(Broad Institute), Cory M. Johannessen(Broad Institute), John G. Doench(Broad Institute), Vamsi K. Mootha(Broad Institute), Gad Getz(Broad Institute), Catherine J. Wu(Broad Institute)
Cancer Cell
September 19, 2019
10.1016/j.ccell.2019.08.005
Cited by 359Open Access
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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.

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