BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer

Cell Rep. 2022 Sep 13;40(11):111304. doi: 10.1016/j.celrep.2022.111304.


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: BRD4; CP: Cancer; MCL1; adaptive responses; apoptosis; bioinformatics; combination therapy; drug resistance; fatty acid pathway; lipids; network models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Cell Line, Tumor
  • ErbB Receptors / metabolism
  • Fatty Acids
  • Female
  • Humans
  • Lipids
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Up-Regulation


  • Fatty Acids
  • Lipids
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • ErbB Receptors