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

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 Biran; Stacey M Fernandes; Jennifer R Brown; Ana Lako; Zoe B Ciantra; Matthew A Lawlor; Derin B Keskin; Namrata D Udeshi; William G Wierda; Kenneth J Livak; Anthony G Letai; Donna Neuberg; J Wade Harper; Steven A Carr; Federica Piccioni; Christopher J Ott; Ignaty Leshchiner; Cory M Johannessen; John Doench; Vamsi K Mootha; Gad Getz; Catherine J Wu

doi:10.1016/j.ccell.2019.08.005

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

Cancer Cell. 2019 Oct 14;36(4):369-384.e13. doi: 10.1016/j.ccell.2019.08.005. Epub 2019 Sep 19.

Authors

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

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; CHU de Clermont-Ferrand, 63000 Clermont-Ferrand, France; Université Clermont Auvergne, EA7453 CHELTER, 63000 Clermont-Ferrand, France.
² Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Instituto de Investigación Biomédica de Salamanca, Centro de Investigación del Cáncer-IBMCC, Universidad de Salamanca, 37007 Salamanca, Spain; Servicio de Hematología, Hospital Universitario de Salamanca, 37007 Salamanca, Spain.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA.
⁹ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
¹⁰ Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹⁴ Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁵ Harvard Medical School, Boston, MA 02215, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02214, USA.
¹⁶ Harvard Medical School, Boston, MA 02215, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Massachusetts General Hospital Cancer Center, Boston, MA 02214, USA.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. Electronic address: cwu@partners.org.

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.

Keywords: AMPK; BCL-2; CRISPR/Cas9; chronic lymphocytic leukemia; clonal evolution; drug resistance; genome-wide screen; metabolism; mitochondrion; venetoclax.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
Cell Line, Tumor
Clonal Evolution / drug effects
Disease Progression
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Energy Metabolism / drug effects
Energy Metabolism / genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Male
Mice
Middle Aged
Mitochondria / drug effects
Mitochondria / pathology*
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Oxidative Phosphorylation / drug effects
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-bcl-2 / metabolism
Sulfonamides / pharmacology*
Sulfonamides / therapeutic use
Treatment Outcome
Xenograft Model Antitumor Assays

Substances

BCL2 protein, human
Bridged Bicyclo Compounds, Heterocyclic
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2
Sulfonamides
venetoclax

Abstract

Publication types

MeSH terms

Substances

Grants and funding