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

Gonghong Yan, Augustin Luna, Heping Wang, Behnaz Bozorgui, Xubin Li, Maga Sanchez, Zeynep Dereli, Nermin Kahraman, Goknur Kara, Xiaohua Chen, Caishang Zheng, Daniel McGrail, Nidhi Sahni, Yiling Lu, Ozgun Babur, Murat Cokol, Bora Lim, Bulent Ozpolat, Chris Sander, Gordon B. MillsAnil Korkut

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Article number111304
Pages (from-to)111304
JournalCell Reports
Issue number11
StatePublished - Sep 13 2022


  • BRD4
  • CP: Cancer
  • MCL1
  • adaptive responses
  • apoptosis
  • bioinformatics
  • combination therapy
  • drug resistance
  • fatty acid pathway
  • lipids
  • network models
  • Up-Regulation
  • Fatty Acids
  • Humans
  • Lipids
  • Myeloid Cell Leukemia Sequence 1 Protein/metabolism
  • Cell Line, Tumor
  • Female
  • ErbB Receptors/metabolism
  • Breast Neoplasms/drug therapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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