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Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies.
- Source :
-
Cancer cell [Cancer Cell] 2019 Oct 14; Vol. 36 (4), pp. 369-384.e13. Date of Electronic Publication: 2019 Sep 19. - Publication Year :
- 2019
-
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.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Apoptosis drug effects
Apoptosis genetics
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 pathology
Male
Mice
Middle Aged
Mitochondria drug effects
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Oxidative Phosphorylation drug effects
Proto-Oncogene Proteins c-bcl-2 metabolism
Sulfonamides therapeutic use
Treatment Outcome
Xenograft Model Antitumor Assays
Antineoplastic Combined Chemotherapy Protocols pharmacology
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
Mitochondria pathology
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 36
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 31543463
- Full Text :
- https://doi.org/10.1016/j.ccell.2019.08.005