Article ; Online: Lactate Utilization Enables Metabolic Escape to Confer Resistance to BET Inhibition in Acute Myeloid Leukemia.
2024 Volume 84, Issue 7, Page(s) 1101–1114
Abstract: Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for ... ...
Abstract | Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment. Significance: Lactate utilization allows AML myeloblasts to maintain metabolic integrity and circumvent antileukemic therapy, which supports testing of lactate utilization inhibitors in clinical settings to overcome BET inhibitor resistance in AML. See related commentary by Boët and Sarry, p. 950. |
|||||
---|---|---|---|---|---|---|
MeSH term(s) | Humans ; Animals ; Mice ; Nuclear Proteins/metabolism ; Transcription Factors/metabolism ; Lactic Acid ; Cell Line, Tumor ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/metabolism ; Lactate Dehydrogenases ; Bromodomain Containing Proteins ; Cell Cycle Proteins | |||||
Chemical Substances | Nuclear Proteins ; Transcription Factors ; Lactic Acid (33X04XA5AT) ; Lactate Dehydrogenases (EC 1.1.-) ; BRD4 protein, human ; Bromodomain Containing Proteins ; Cell Cycle Proteins | |||||
Language | English | |||||
Publishing date | 2024-01-30 | |||||
Publishing country | United States | |||||
Document type | Journal Article | |||||
ZDB-ID | 1432-1 | |||||
ISSN | 1538-7445 ; 0008-5472 | |||||
ISSN (online) | 1538-7445 | |||||
ISSN | 0008-5472 | |||||
DOI | 10.1158/0008-5472.CAN-23-0291 | |||||
Shelf mark |
|
|||||
Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
Uh III Zs.135/5: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.