Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Cancer Cell ; 36(4): 369-384.e13, 2019 10 14.
Article in English | MEDLINE | ID: mdl-31543463

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.


Subject(s)
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 , 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
SELECTION OF CITATIONS
SEARCH DETAIL
...