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

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. [Display omitted] • MCL1-driven apoptosis evasion is an adaptive response to BET inhibition (BETi) • Co-targeting MCL1 and BET is highly synergistic in breast cancer cells • MCL1 copy-number alterations can predict responses to BET and MCL1 targeting • Activities of fatty acid synthesis and RTK pathways link BETi to apoptosis evasion Yan et al. show that pharmacological co-targeting of MCL1 and BET is highly effective in breast cancer cells. The proposed combination therapy may be effective for treatment of patients with aggressive subtypes of breast cancers whose tumors carry genetic aberrations associated with cell-death evasion. [ABSTRACT FROM AUTHOR]