Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [ChIP-Seq]

Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance.