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Nature. 2016 Jan 21;529(7586):413-417. doi: 10.1038/nature16508. Epub 2016 Jan 6.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts USA.
4
Princess Margaret Cancer Center/University Health Network, Toronto, Ontario, M5G1L7, Canada.
5
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G2M9, Canada.
6
Harvard University, Cambridge, Massachusetts, USA.
7
Cancer Research UK, Cambridge Institute, University of Cambridge, UK, CB2 0RE.
8
Department of Pathology, Brigham and Women's Hospital, and Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
9
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
10
Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
11
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
12
Broad Institute, Cambridge, Massachusetts, USA.
#
Contributed equally

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.

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PMID:
26735014
PMCID:
PMC4854653
DOI:
10.1038/nature16508
[Indexed for MEDLINE]
Free PMC Article

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