Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

BET inhibitors that target bromodomain chromatin readers such as BRD4 are being explored as potential therapeutics in cancer; here triple-negative breast cancer cell lines are shown to respond to BET inhibitors and resistance seems to be associated with transcriptional changes rather than drug efflux and mutations, opening potential avenues to improve clinical responses to BET inhibitors. BET inhibitors that target bromodomain chromatin readers such as BRD4 are being explored as potential therapeutics in cancer. Here Kornelia Polyak and colleagues investigate the response of breast cancer cell lines and xenograft mouse models to BET inhibitors. They find that triple-negative breast cancer cell lines respond to BET inhibitors. Resistance can emerge, but there is no evidence for mechanisms involving drug efflux or mutations in the bromodomain genes or known driver genes. Instead, there are transcriptional changes and increased recruitment of BRD4 to chromatin independent of its bromodomain, concomitant with its increased phosphorylation. Together with two recent Nature publications from the laboratories of Mark Dawson and Johannes Zuber dealing with different cancers, the study suggests potential avenues to improve clinical responses to BET inhibitors. Jeff Settleman discusses all three papers in News & Views. Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy1,2,3. BET bromodomain inhibitors, which have shown efficacy in several models of cancer4,5,6, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs7,8,9. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.