Abstract
<h3>Abstract</h3> We have demonstrated that adaptive responses to BET inhibitors induce a therapeutic vulnerability to the combination of BET and MCL1 inhibitors in breast cancer. Our generalizable strategy for identification of adaptive responses and therapeutic vulnerabilities integrates our novel network analysis method, termed Target Score, with genomics and mechanistic perturbation biology studies. In drug resistant cells, adaptive responses to BET inhibitors involve upregulation of fatty acid metabolism coupled to changes in membrane fluidity, cell adhesion and motility, EGFR/HER2 pathway activation, and subsequent accumulation of MCL1 that drives apoptosis evasion. The combined inhibition of MCL1 and BET proteins is highly synergistic in diverse breast cancer models. MCL1 inhibition was found to be most effective, either as a single agent or in combination in tumors with MCL1 chromosomal amplifications, a frequent driver aberration in breast cancer. In conclusion, we have discovered a mechanism of resistance to BET inhibition and an anti-resistance combination therapy that can increase the therapeutic benefit for a significant fraction of breast cancer patients.
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