BET Degradation Is More Effective Than Competitive Inhibition in T-ALL

Inhibitors of the bromodomain and extra-terminal domain (BET) family proteins disrupt chromatin-dependent transcriptional signaling, which is often dysregulated in cancer. Competitive BET inhibitors, such as JQ1, bind the bromodomain of the BET protein BRD4 to promote its release from chromatin, predominantly at superenhancers, to selectively suppress transcription of target genes. A small-molecule BET degrader (dBET1) has recently been developed that has a more robust antiproliferative effect than competitive BET inhibition in models of acute myeloid leukemia, but the underlying mechanism is unknown. Winter, Mayer, Buckley, and colleagues explored the mechanism underlying the differences between competitive BET inhibition and BET degradation in models of T-cell acute lymphoblastic leukemia (T-ALL). Chemical optimization of dBET1 led to the identification of a more potent compound called dBET6, which was more cell-permeable and exhibited greater cytotoxicity than dBET1. In a panel of 20 T-ALL cell lines, dBET6 also more potent than dBET1 and induced BRD4 degradation, c-MYC downregulation, and apoptosis. Further, dBET6 reduced tumor burden and extended survival in a mouse model of T-ALL to a greater extent than JQ1. JQ1 preferentially displaced BRD4 from superenhancers and downregulated a discrete set of superenhancer-regulated genes, whereas dBET6 induced a global depletion of BRD4 from regulatory elements and strong downregulation of the T-ALL core regulatory circuitry transcription factors. Mechanistically, dBET6 induced a global disruption in transcription elongation that was independent of P-TEFb and its kinase subunit CDK9, which control the release of promoter-proximal pausing. In addition to suggesting that the BET proteins are master regulators of productive transcription elongation, these findings indicate that inhibitors that degrade BET proteins may be more effective than competitive inhibitors and merit further development for the treatment of patients with cancer.

Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, et al. BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment. Mol Cell 2017;67:5–18.e19.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.