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

Nature
Authors
Keywords
Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, 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 programs. 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.

Year of Publication
2016
Journal
Nature
Volume
529
Issue
7586
Pages
413-7
Date Published
2016 Jan 21
ISSN
1476-4687
URL
DOI
10.1038/nature16508
PubMed ID
26735014
PubMed Central ID
PMC4854653
Links
Grant list
CA103867 / CA / NCI NIH HHS / United States
P01 CA080111 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
P50 CA168504 / CA / NCI NIH HHS / United States
CA168504 / CA / NCI NIH HHS / United States
CA120184 / CA / NCI NIH HHS / United States
CA080111 / CA / NCI NIH HHS / United States
R01 CA103867 / CA / NCI NIH HHS / United States