Faculty, Staff and Student Publications
Publication Date
9-13-2022
Journal
Cell Reports
Abstract
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
Breast Neoplasms, Cell Line, Tumor, ErbB Receptors, Fatty Acids, Female, Humans, Lipids, Myeloid Cell Leukemia Sequence 1 Protein, Up-Regulation, BRD4, CP: Cancer, MCL1, adaptive responses, apoptosis, bioinformatics, combination therapy, drug resistance, fatty acid pathway, lipids, network models
DOI
10.1016/j.celrep.2022.111304
PMID
36103824
PMCID
PMC9523722
PubMedCentral® Posted Date
9-30-2022
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons