期刊
NATURE
卷 529, 期 7586, 页码 413-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature16508
关键词
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资金
- NIH DF/HCC SPORE in Breast Cancer [CA168504, CA080111, CA103867]
- Susan G. Komen Foundation
- CPRIT [RP110471, RP140367]
- Welch Foundation
- US Department of Defense CDMRP [BC122003, CA120184]
- Princess Margaret Cancer Foundation
- Canada Foundation for Innovation
- Ontario Research Fund [CFI32372]
- NSERC discovery grant [RGPIN-2015-04658]
- Harvard Ludwig Center for Cancer Research
- Cancer Research UK [22310, 20411] Funding Source: researchfish
Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy(1-3). BET bromodomain inhibitors, which have shown efficacy in several models of cancer(4-6), 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(7-9). 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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