Bet on drug resistance

Inhibitors of the BET bromodomain proteins are promising cancer therapeutics, but tumour cells are likely to become resistant to these drugs. Anticipated mechanisms of resistance have now been described. See Letter p.413 The roots of resistance 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.