Quantitative analysis of bi-modal binding of BET proteins at promoters predicts I-BET sensitivity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA494237 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7947470.fastq.gz | Fastqsanger.gz | |||
| SRR7947480.fastq.gz | Fastqsanger.gz | |||
| SRR7947490.fastq.gz | Fastqsanger.gz | |||
| SRR7947500.fastq.gz | Fastqsanger.gz | |||
| SRR7947510.fastq.gz | Fastqsanger.gz |
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Project description:We identified a chromatin displacement signature for the bromodomain proteins BRD2, BRD3 and BRD4 at TSS following treatment with I-BET152, an inhibitor of BET proteins. By integrating ChIP-seq, RNA-seq and Chem-seq data, we correlated alteration of the BRD4 signature at TSS with strong downregulation of gene expression which will facilitate identification of markers of sensitivity and resistance to drug.
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Project description:BET inhibitors have been tested in several clinical trials, and despite encouraging results from preclinical cancer models, substantial clinical benefit in monotherapy has been limited. An important aspect is the proper translation of preclinical observations into clinical evaluation. The clinical BET inhibitor BI 894999 was tested in mechanistic studies, assessing pathway modulation and rational drug combinations at clinically achievable concentrations. We used NUT carcinoma (NC) cell lines with bona fide oncogenic drivers fusions including BRD4-NUT and BRD3-NUT. Proliferation assays, pathway modulation studies, and in vivo xenografts were performed with BI 894999, in monotherapy, and in combination with the clinical p300/CBP inhibitor CCS1477. Detachment of the BET complex from chromatin in vitro was assessed by LSM immunofluorescence, and by immunohistochemistry in tumour sections. Clinical findings on pathway modulation marker such as HEXIM1 and HIST2H2BF as well as human PK data were back translated to the preclinic setting. The clinical phase I scheduling regimen of 1 week-on (with a loading dose on day 1) and one week-off, derived from modelling of preclinical and clinical data, achieved plasma levels of about 20 nM. This concentration led to the full removal of BRD-NUT from chromatin and resulted in sustained and prolonged PD modulation of HEXIM1 and HIST2H2BF, accompanied with better patient tolerability. Rational combination with the p300/CBP inhibitor CCS1477 led to tumour regression in all three NC xenograft models tested. Preclinical mechanistic studies with the BET inhibitor BI 894999, back translation of clinical PK/PD data, and modelling provided guidance for an optimal clinical schedule. BI 894999 holds significant potential as a combination drug and preclinical data identified p300/CBP inhibitors as highly relevant combination partner for NUT carcinoma and beyond, pending clinical trials.
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Project description:Interactions between a new potent Bromodomain and extraterminal domain (BET) inhibitor BI 894999 and the polo-like kinase (PLK) inhibitor volasertib were studied in acute myeloid leukemia cell lines in vitro and in vivo. We provide data for the distinct mechanisms of action of these two compounds with a potential utility in AML based on gene expression, cell cycle profile and modulation of PD biomarkers such as MYC and HEXIM1. In contrast to BI 894999, volasertib treatment neither affects MYC nor HEXIM1 expression, but augments and prolongs the decrease of MYC expression caused by BI 894999 treatment. In vitro combination of both compounds leads to a decrease in S-Phase and to increased apoptosis. In vitro scheduling experiments guided in vivo experiments in disseminated AML mouse models. Co-administration of BI 894999 and volasertib dramatically reduces tumor burden accompanied by long-term survival of tumor-bearing mice and eradication of AML cells in mouse bone marrow. Together, these preclinical findings provide evidence for the strong synergistic effect of BI 894999 and volasertib, warranting future clinical studies in patients with AML to investigate this paradigm.
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Project description:Therapeutic impact of BET inhibitor BI 894999 treatment: backtranslation from the clinic
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Project description:Bromodomain and extra-terminal (BET) protein inhibitors have been reported as treatment options for acute myeloid leukemia (AML) in preclinical models and are currently being evaluated in clinical trials. This work presents a novel potent and selective BET inhibitor (BI 894999), which has recently entered clinical trials (NCT02516553). In preclinical studies, this compound is highly active in AML cell lines, primary patient samples, and xenografts. HEXIM1 is described as an excellent pharmacodynamic biomarker for target engagement in tumors as well as in blood. Mechanistic studies show that BI 894999 targets super-enhancer-regulated oncogenes and other lineage-specific factors, which are involved in the maintenance of the disease state. BI 894999 is active as monotherapy in AML xenografts, and in addition leads to strongly enhanced antitumor effects in combination with CDK9 inhibitors. This treatment combination results in a marked decrease of global p-Ser2 RNA polymerase II levels and leads to rapid induction of apoptosis in vitro and in vivo. Together, these data provide a strong rationale for the clinical evaluation of BI 894999 in AML.
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Project description:We have identified a cluster of ELOA3 gene homologs that are activated upon treatment with BET bromodomain inhibitors and mediate sensitivity to BET inhibition.
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It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition.These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.
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Project description:Small molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are in clinical trials for a variety of cancers, but patient selection strategies are limited. This is due in part to the heterogeneity of response following BET inhibition (BETi), which includes differentiation, senescence, and cell death in subsets of cancer cell lines. To elucidate the dominant features defining response to BETi, we carried out phenotypic and gene expression analysis of both treatment naïve cell lines and engineered tolerant lines. We found that both de novo and acquired tolerance to BET inhibition are driven by the robustness of the apoptotic response and that genetic or pharmacological manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further identify that ordered expression of the apoptotic genes BCL2, BCL2L1, and BAD significantly predicts response to BETi. Our findings highlight the role of the apoptotic network in response to BETi, providing a molecular basis for patient stratification and combination therapies. Gene expression profiling of A375 melanoma cells or NOMO-1 AML cells treated with DMSO or the BET inhibitor, CPI203. Also, gene expression profiling of the respective derived BETi-tolerant cells treated with DMSO or CPI203.
2016-01-07 | E-GEOD-69383 | biostudies-arrayexpress
Project description:Bromodomain and extra-terminal domain (BET) family inhibitors offer a new approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML) that are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3â to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter and CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2 that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was up-regulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET inhibitor-induced cell death. Kasumi-1 cells were treated with DMSO, 250 nM JQ1, and 125 nM MS417 for 1 and 3 hours, and PRO-seq was performed to study transcriptional changes. Kasumi-1 cells were treated with 250 nM JQ1 for 0, 15, and 30 minutes, and PRO-seq was performed. Two biological replicates were included for each time point. Primary AML patient cells were treated with DMSO and 250 nM JQ1 for 1 hour, and PRO-seq was performed to confirm trancriptional effects of BET inhibitors.
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Project description:Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.
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