Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of targetable epigenetic vulnerabilities for uveal melanoma

ABSTRACT: Uveal melanoma (UM) is the most common adult primary intraocular malignancy, with a strong predilection for hepatic metastasis, occurring in approximately 50% of cases. Metastatic UM remains highly resistant to therapy and is almost invariably fatal. The strongest genetic driver of UM metastasis is loss of function of the tumor suppressor BRCA-associated protein 1 (BAP1), which leads to widespread epigenetic dysregulation. To identify novel therapeutic strategies, we investigated whether targeting the epigenome could reveal new vulnerabilities in UM. We performed high-throughput compound screening using a curated epigenetic inhibitor library and identified BET (bromodomain and extra-terminal domain) inhibition as a particularly promising approach. While previous clinical trials with BET inhibitors for UM treatment have failed clinically, we found substantial heterogeneity in the efficacy of different BET inhibitors in UM. Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and prevented detectable metastases in the bones, spinal cord, and brain. Transcriptomic analysis revealed a strong overlap between BET inhibition and histone deacetylase (HDAC) inhibition-- an approach currently under clinical evaluation for UM treatment. BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuron-like phenotype in UM cells. These findings establish BET inhibition as a potent and previously underappreciated vulnerability for metastatic UM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300710 | GEO | 2025/06/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Contribution of BET proteins to androgen (DHT)-stimulated gene expression program

Project description:Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and heme malignancies. BET family member BRD4 function at enhancers/super-enhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here we tested the hypothesis that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the Androgen Receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075. DHT-stimulated transcription of AR target genes was inhibited by ABBV-075 without significant effect on AR protein expression. Further, ABBV-075 disrupted DHT-stimulated recruitment of BET family member BRD4 to gene regulatory regions co-occupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition disrupted the composition and function of AR occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and inhibition of eRNA transcription. ABBV-075 displayed potent anti-proliferative activity in multiple models of resistance to second generation anti-androgens and inhibited the activity of AR-V7 and the AR LBD gain-of-function mutations, F877L and L702H. ABBV-075 was also a potent inhibitor of MYC and the TMPRSS2-ETS fusion protein, important parallel transcription factor drivers of CRPC.

2017-02-21 | GSE86245 | GEO

Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cell line

Project description:We comprehensively analyzed the differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) underlying the antitumor functions of BET inhibitors of human HCC cells using RNA sequencing (RNA-Seq). The pan-BET inhibitor ABBV-075 and BD2 specific inhibitor ABBV-744 attenuates the IFNγ-induced inflammatory response. In addition, BD2 inhibitors were predominantly effective in inflammatory response.

2022-05-04 | GSE189376 | GEO

Identification of potential ABBV-075 responsive markers in human PBMCs

Project description:To identify genes that are modulated by BET inhibitors in blood, we determined global gene expression changes in ABBV-075-treated human PBMC samples

2017-03-07 | GSE89933 | GEO

Identification of potential ABBV-075 responsive markers in mouse whole blood

Project description:To identify genes that are modulated by BET inhibitors in blood, we determined global gene expression changes in ABBV-075-treated mouse whole blood samples

2017-03-07 | GSE89935 | GEO

Epigenetic library screen reveals novel targets for uveal melanoma

Project description:Uveal melanoma (UM) is the most common primary ocular cancer in adults, which metastasizes mainly to the liver in around half of the cases. The limited potency of current treatment options for metastatic UM necessitates an urgent exploration of novel therapeutic approaches to improve patient prognosis. We conducted a large epigenetic compound library screen with the currently most well characterized, focused epigenetics library available, which consists of 932 potent, cell permeable, medically active, epigenetic-directed small molecule modulators. Our screening identified two new lead compounds, which so-far have been unappreciated for UM. Romidepsin, an HDAC inhibitor with specificity for class I HDACs, was the most efficient compound in-vitro, as well as the BET inhibitor Mivebresib, which showed minimal toxicity on normal cells. RNA sequencing and pathway analysis revealed an upregulation of PRC-associated gene targets induced by HDAC inhibition, while BET inhibition appears to act through retinoic acid related pathways. Mivebresib treatment in a metastatic uveal melanoma mouse model resulted in longer survival times and reduced metastasis to the spinal cord and brain. The results of our drug screen indicate a vulnerability for HDAC and BET inhibition for UM cells. The BET inhibitor Mivebresib may be a promising candidate for future synergistic and clinical trials.

2025-04-22 | GSE294950 | GEO

Selective inhibition of the second bromodomain of BET family proteins results in robust antitumor activity in preclinical models of acute myeloid leukemia

Project description:Dual bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first and second bromodomains across BRD2, BRD3, BRD4 and BRDt only displayed modest activity as monotherapy in clinical trials. Thrombocytopenia, closely followed by symptoms characteristic of GI toxicity, have presented as dose limiting adverse events that may prevented escalation to higher dose levels for more robust efficacy. ABBV-744 is a highly selective inhibitor for the second bromodomain (BD2) of the four BET family proteins. In contrast to the broad antiproliferative activities observed with DbBi, ABBV-744 displayed significant antiproliferative activities largely but not exclusively in cancer cell lines derived from AML and androgen receptor (AR) positive prostate cancer. Studies in AML xenograft models demonstrated anti-tumor efficacy for ABBV-744 that was comparable to the pan-BET inhibitor ABBV-075 but with improved tolerability. Enhanced anti-tumor efficacy was also observed with the combination of ABBV-744 and the Bcl-2 inhibitor, venetoclax (ABT-199) compared to monotherapies of either agent alone. These results collectively support the clinical evaluation of ABBV-744 in AML (Clinical Trials.gov identifier: NCT03360006).

2021-01-31 | GSE144326 | GEO

Selective Inhibition of the Second Bromodomain of BET Family Maintains Anti-Tumor Efficacy and Improves Tolerability (LNCaP RNA-seq)

Project description:Here we report the discovery of ABBV-744, a first in class, highly potent and selective inhibitor of BET family BD2 domains with drug like properties. RNA-seq analysis revealed that ABBV-744 elicited potent inhibition of AR-dependent transcription without causing broad transcription alterations associated with exposure to pan BET inhibitors.

2019-02-04 | GSE118152 | GEO

Selective Inhibition of the Second Bromodomain of BET Family Maintains Anti-Tumor Efficacy and Improves Tolerability (22RV1 RNA-seq)

2019-10-23 | GSE130247 | GEO

Selective Inhibition of the Second Bromodomain of BET Family Maintains Anti-Tumor Efficacy and Improves Tolerability

Project description:Here we report the discovery of ABBV-744, a first in class, highly potent and selective inhibitor of BET family BD2 domains with drug like properties. ChIP-seq analysis revealed that ABBV-744 displaced BRD4 from AR-containing super enhancers and elicited potent inhibition of AR-dependent transcription without causing broad transcription alterations associated with exposure to pan BET inhibitors.

2020-01-22 | GSE118247 | GEO

Identification of potential ABBV-075 responsive markers in mouse skin

Project description:Determination of transcriptional alterations in skin samples from ABBV-075 treated mice

2017-03-07 | GSE89934 | GEO