BET inhibition in ovarian cancer (i-BET858, i-BET151)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA731034 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Ovarian cancer cell line OVCAR-3 was treated with two different BET inhibitors for 4 and 24 hours.
2023-04-17 | GSE174670 | GEO
Project description:Small molecule inhibition of the BET family of proteins, which bind acetylated lysines within histones, has been shown to have a marked therapeutic benefit in pre-clinical models of MLL-fusion protein driven leukemias. Here, we report that I-BET151, a highly specific BET family bromodomain inhibitor, leads to growth inhibition in a human erythroleukemic (HEL) cell line as well as in erythroid precursors isolated from polycythemia vera patients. One of the genes most highly down regulated by I-BET151 was LMO2, an important oncogenic regulator of hematopoietic stem cell development and erythropoiesis. We previously reported that LMO2 transcription is dependent upon JAK2 kinase activity in HEL cells. Here, we show that the transcriptional changes induced by a JAK2 inhibitor (TG101209) and I-BET151 in HEL cells are significantly over-lapping, suggesting a common pathway of action. We generated JAK2 inhibitor resistant HEL cells and showed that these retain sensitivity to I-BET151. These data highlight I-BET151 as a potential alternative treatment against myeloproliferative neoplasms driven by constitutively active JAK2 kinase.
2013-08-20 | E-MTAB-1817 | biostudies-arrayexpress
Project description:Small molecule BET bromodomain inhibitors (BETi) are actively being pursued in clinical trials for the treatment of a variety of cancers, however, the mechanisms of resistance to targeted BET protein inhibitors remain poorly understood. Using a novel mass spectrometry approach that globally measures kinase signaling at the proteomic level, we evaluated the response of the kinome to targeted BET inhibitor treatment in a panel of BRD4-dependent ovarian carcinoma (OC) cell lines. Despite initial inhibitory effects of BETi, OC cells acquired resistance following sustained treatment with the BETi, JQ1. Through application of Multiplexed Inhibitor Beads (MIBs) and mass spectrometry, we demonstrate that BETi resistance is mediated by adaptive kinome reprogramming, where activation of compensatory pro-survival kinase networks overcomes BET protein inhibition. Furthermore, drug combinations blocking these kinases may prevent or delay the development of drug resistance and enhance the efficacy of BET inhibitor therapy. RNAseq was employed to identify changes in kinase RNA expression following short term (48h) or chronic (JQ1R) JQ1 treatment in three different ovarian cancer cell lines.
2016-07-21 | E-GEOD-82329 | biostudies-arrayexpress
Project description:The MYC transcription factor is a master regulator of diverse cancer pathways and somatic cell reprogramming. MYC is a compelling therapeutic target that exhibits cancer-specific cellular effects. Pharmacologic inhibition of MYC function has proven challenging due to its numerous modes of forced expression and the difficulty of disrupting protein-DNA interactions. Here we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule bromodomain inhibitors of the BET family of chromatin adaptors. This transcriptional suppression of MYC was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from growth suppression by BET inhibitors and revealed that MYC exerts a direct and tight control of key pro-growth and anti-apoptotic target genes. Transcriptional profiling of two cells after 4 and 8 hours of treatment with BET inhibitor shows that both MYC and its targets are strongly down-regulated. We thus demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains, and suggest that such inhibitors may have broad clinical applicability given the widespread pathogenetic role of MYC in cancer. LP-1, a multiple myeloma cell line, and Raji, a Burkitt lymphoma cell line, were treated with BET inhibitor and an inactive enantiomer for 4 or 8 hours. Two biological replicates of each sample were profiled on exon arrays.
2011-09-18 | E-GEOD-29449 | biostudies-arrayexpress
Project description:Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically-defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis demonstrated downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knock-down phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in three in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma. Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anti-cancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, demonstrate a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. JQ1 is a novel thieno-triazolo-1,4-diazepine, which displaces BET bromodomains from chromatin by competitively binding to the acetyl lysine recognition pocket. BE(2)-C and Kelly cells were treated in triplicate with 1 µM JQ1 or DMSO for 24 hours. RNA was extracted and a decrease in MYCN transcript was confirmed by real time RT-PCR as described above. The samples were profiled using the Affymetrix PrimeView Human Gene Expression Array (Affymetrix) at Beth Israel Deaconess Medical Center (Boston, MA, USA).
2013-02-25 | E-GEOD-43392 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to a potential application of bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and onset of fibrosis) to assess its potential effectiveness for the treatment of NASH and liver fibrosis. I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization through RNA-sequencing pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis following treatment, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.
2018-11-27 | GSE114261 | GEO
Project description:The emergence of tumor cells with certain stem-like characteristics such as high aldehyde dehydrogenase (ALDH) activity contributes to chemotherapy resistance. Here we report that inhibition of the BET protein BRD4 potentiates the tumor suppressive effects of cisplatin by targeting ALDH activity. The clinically applicable small molecule BET inhibitor JQ1 synergized with cisplatin by suppressing the growth of epithelial ovarian cancer cells both in vitro and in vivo. This correlated with the suppression of ALDH activity and ALDH1A1 gene expression. BRD4 regulates ALDH1A1 gene transcription through a super-enhancer and expression of its associated enhancer RNA. Thus, targeting the BET protein BRD4 using clinical applicable small molecule inhibitors such as JQ1 is a promising strategy to enhance cisplatin response.
2017-02-05 | GSE77568 | GEO
Project description:Epigenetic regulators have emerged as exciting targets for cancer therapy. Additionally, restoration of antitumor immunity by blocking the PD-L1 signaling using antibodies has proven to be beneficial in cancer therapy. Here we show that BET bromodomain inhibition suppresses PD-L1 expression and restores antitumor immunity in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of antitumor cytotoxic T cells. Together, these data demonstrate an epigenetic approach to block PD-L1 signaling to restore antitumor immunity. Given the fact that BET inhibitors have been proven safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a novel treatment strategy for targeting PD-L1 expression.
2016-10-17 | GSE81698 | GEO
Project description:Background: Epigenetic mechanisms are implicated in chronic inflammatory pathogenesis. Bromodomain Extra-Terminal (BET) proteins are druggable epi-reader proteins which bind acetylated histones and transcription factors regulating gene expression, including inflammatory genes. Objectives: To evaluate the role of specific histone acetylation events and BET protein interactions in promoting keratinocyte inflammatory and transcriptional responses, to determine the effects of pharmacological inhibition of BET proteins and thereby test the hypothesis that BET proteins represent an effective therapeutic target to treat cutaneous inflammation. Methods: Primary human keratinocytes were stimulated with tumour necrosis factor alpha and interleukin 17 (TNFalpha + IL-17), +/- BET inhibitor (I-BET151). Cytokine induced interleukin 6 and 8 (IL-6 /-8) responses were determined by qPCR and ELISA. Chromatin immunoprecipitation (ChIP) assays were undertaken to characterise epigenetic changes at the IL-6 and IL-8 gene promoters, while the effect of I-BET151 treatment on keratinocyte transcriptional response was determined by Illumina array. Results: TNFalpha + IL-17 induced gene-specific epigenetic changes, including: histone hyperacetylation, recruitment of BET proteins (BRD2/3/4) to the promoter regions of IL-6/-8 and activation of RNA polymerase II (PolII(S2P)), correlating with increased IL-6/-8 expression. I-BET151 reduced recruitment of BRD4 and activation of PolII(S2P), at the IL-6 promoter, and BRD3/4 and PolII(S2P), at the IL-8 promoter; which is consistent with I-BET151 inhibitory effects on TNFalpha + IL-17-induced IL-6/-8 expression. A ~10-fold enrichment of BRD4/p65 was observed at the IL-6 promoter compared to the IL-8 promoter. Transcriptomics analysis showed that I-BET151 modulated expression of genes involved in cell cycle, cell proliferation and the innate immune response in keratinocytes stimulated with TNFalpha + IL-17. Conclusions: In human keratinocytes, disease-relevant stimuli induced dynamic epigenetic changes at inflammatory gene loci. BET proteins played a critical role in keratinocyte innate immune responses and displayed differential effects; for example BRD4/p65 was particularly enriched at the IL-6 promoter, indicating that BRD4 may be a critical factor in integrating inflammatory stimuli via NF-B in chronic skin inflammation. Inhibition of these responses by I-BET151 highlights BET proteins as potential therapeutic targets in inflammatory skin disease.
2020-12-31 | GSE155484 | GEO