.png){kind=icon}
.png){kind=icon}
Return
BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer
.png){kind=icon}
OA
AI
DOI：10.1016/j.celrep.2022.111304.png)
.png){kind=icon}
.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation of and vulnerability to the inhibition of MCL1. Drug response and genomics analyses reveal that MCL1 copy-number alterations are associated with effective BET and MCL1 co-targeting. The high frequency of MCL1 chromosomal amplifications (>30%) in basal-like breast cancers suggests that BET and MCL1 co-targeting may have therapeutic utility in this aggressive subtype of breast cancer.
Keywords:
STEAROYL-COA DESATURASE
ADAPTIVE RESISTANCE
APOPTOSIS
ACTIVATION
EXPRESSION
RECEPTOR
KINASE
AI Summary
Key information extracted from the uploaded paper, including a brief overview, abstract, background, key highlights, visual analysis, and future outlook.
Journal
IF:
6.9
Papers:
1.7W
Citations:
10.2W
View more organizations