Non-canonical transcriptional consequences of BET inhibition in cancer.

Inhibition of the bromo and extra-terminal domain (BET) protein family in preclinical studies has demonstrated that BET proteins are critical for cancer progression and important therapeutic targets. Downregulation of the MYC oncogene, CDK6, BCL2 and FOSL1 are just a few examples of the effects of BET inhibitors that can lead to cell cycle arrest and apoptosis in cancer cells. However, BET inhibitors have had little success in the clinic as a single agent, and there are an increasing number of reports of resistance to BET inhibition emerging after sustained treatment of cancer cells in vitro. Here we summarize the non-canonical consequences of BET inhibition in cancer, and discuss how these may both lead to resistance and inform rational combinations that could greatly enhance the clinical application of these inhibitors.