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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Azepines / pharmacology*
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Azepines / therapeutic use*
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Binding, Competitive / drug effects
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Casein Kinase II / metabolism
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Chromatin / genetics
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Chromatin / metabolism
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Epigenesis, Genetic / drug effects
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Epigenesis, Genetic / genetics
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Genome, Human / drug effects
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Genome, Human / genetics
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Humans
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Mediator Complex Subunit 1 / metabolism
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Mice
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Phosphorylation / drug effects
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Phosphoserine / metabolism
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Protein Binding / drug effects
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Protein Phosphatase 2 / metabolism
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Protein Structure, Tertiary / drug effects*
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Proteomics
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic / drug effects
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Triazoles / pharmacology*
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Triazoles / therapeutic use*
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Triple Negative Breast Neoplasms / drug therapy*
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Triple Negative Breast Neoplasms / genetics
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Triple Negative Breast Neoplasms / metabolism
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Triple Negative Breast Neoplasms / pathology
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Xenograft Model Antitumor Assays
Substances
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(+)-JQ1 compound
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Azepines
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BRD4 protein, human
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Cell Cycle Proteins
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Chromatin
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MED1 protein, human
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Mediator Complex Subunit 1
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Nuclear Proteins
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Transcription Factors
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Triazoles
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Phosphoserine
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Casein Kinase II
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Protein Phosphatase 2