Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer
Open accessAbstract
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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From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [191]
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- Authors
- Shu, S., Lin, C. Y., He, H. H., Witwicki, R. M., Tabassum, D. P., Roberts, J. M., Janiszewska, M., Jin Huh, S., Liang, Y., Ryan, J., Doherty, E., Mohammed, H., Guo, H., Stover, D. G., Ekram, M. B., Peluffo, G., Brown, J., D’Santos, C., Krop, I. E., Dillon, D., McKeown, M., Ott, C., Qi, J., Ni, M., Rao, P. K., Duarte, M., Wu, S.-Y., Chiang, C.-M., Anders, L., Young, R. A., Winer, E. P., Letai, A., Barry, W. T., Carroll, J. S., Long, H. W., Brown, M., Shirley Liu, X., Meyer, C. A., Bradner, J. E., & Polyak, K.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- University Health Network (CA)
- Harvard University (US)
- University of Cambridge (GB)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Whitehead Institute for Biomedical Research (US)
- Broad Institute (US)
- Corresponding author
- Bradner, James E.
- ORCID
- Shu, Shaokun
- Lin, Charles Y.
- He, Housheng Hansen
- Roberts, Justin M.
- Janiszewska, Michalina
- Liang, Yi
- Ryan, Jeremy
- Mohammed, Hisham
- Guo, Hao
- Stover, Daniel G.
- Ekram, Muhammad B.
- Peluffo, Guillermo
- Brown, Jonathan
- D’Santos, Clive
- Krop, Ian E.
- Dillon, Deborah
- McKeown, Michael
- Ott, Christopher
- Qi, Jun
- Ni, Min
- Wu, Shwu-Yuan
- Chiang, Cheng-Ming
- Young, Richard A.
- Winer, Eric P.
- Carroll, Jason S.
- Long, Henry W.
- Brown, Myles
- Meyer, Clifford A.
- Bradner, James E.
- Venue
- Nature
- Published
- 2016-01
- Volume
- 529
- Issue
- 7586
- Pages
- 413-417
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4854653
- OpenAlex
- W2226721679
- Cited by
- 632
- References
- 36
- Citations by year
- 2026: 38 · 2025: 52 · 2024: 49 · 2023: 62 · 2022: 60 · 2021: 74 · 2020: 64 · 2019: 68 · 2018: 70 · 2017: 56 · 2016: 38
- FWCI
- 40.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- U.S. Department of Defense
- Susan G. Komen for the Cure
- Cancer Prevention and Research Institute of Texas (RP140367, RP110471)
- Dana-Farber/Harvard Cancer Center
- Princess Margaret Cancer Foundation
- Cancer Research UK (20411, 22310)
- National Institutes of Health (CA080111)
- Ludwig Center at Harvard
- Natural Sciences and Engineering Research Council of Canada (RGPIN-2015, rgpin-2015-04658)
- National Human Genome Research Institute (R01HG002668)
- National Cancer Institute (CA103867, R01CA103867, CA168504, CA080111, CA120184, P01CA080111, P30CA014051, P50CA168504)
- Congressionally Directed Medical Research Programs (CA120184)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- BET inhibitors, triple-negative breast cancer, BRD4, drug resistance, acquired resistance, MED1, protein phosphatase 2A, gene expression changes, xenograft models, combination therapy
- MeSH terms
- Bromodomain Containing Proteins, Animals, Azepines, Binding, Competitive, Chromatin, Female, Humans, Nuclear Proteins, Phosphorylation, Phosphoserine, Protein Binding, Transcription Factors, Transcription, Genetic, Triazoles, Genome, Human, Gene Expression Regulation, Neoplastic, Protein Structure, Tertiary, Cell Cycle Proteins, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Proteomics, Epigenesis, Genetic, Cell Line, Tumor, Casein Kinase II, Cell Proliferation, Mice, Protein Phosphatase 2, Mediator Complex Subunit 1, Triple Negative Breast Neoplasms
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