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Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116919 | GEO | 2019/07/09

REPOSITORIES: GEO

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Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination (RNAseq)

Project description:Three triple negative breast cancer cell lines (MDAMB231, SUM159, and HCC1806) were treated with small molecule inhibitors (JQ1, BET bromodomain inhibitor; GSK2801, BAZ2A/B bromodomain inhibitor) alone and in combination for 72 hours

2019-07-09 | GSE116907 | GEO

Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination (ChIPseq)

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Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination

Project description:Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination

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

Project description: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.

| S-EPMC4854653 | biostudies-literature

Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination (RNAseq)

Project description:Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination (RNAseq)

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Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination (ChIPseq)

Project description:Response of triple negative breast cancer to BAZ2A/B inhibition and BET bromodomain inhibition alone and in combination (ChIPseq)

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Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer.

Project description:BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired.

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

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-01-07 | E-GEOD-63584 | biostudies-arrayexpress

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-01-07 | GSE63584 | GEO

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer [RNA-Seq]

Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. RNA-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment over time

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