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MYC family amplification dictates sensitivity to BET bromodomain protein inhibitor Mivebresib (ABBV-075) in small cell lung cancer

ABSTRACT: MYC family amplification dictates sensitivity to BET bromodomain protein inhibitor Mivebresib (ABBV-075) in small cell lung cancer

PROVIDER: PRJNA962070 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24312415_1.fastq.gz	Fastqsanger.gz
	SRR24312415_2.fastq.gz	Fastqsanger.gz
	SRR24312417_1.fastq.gz	Fastqsanger.gz
	SRR24312417_2.fastq.gz	Fastqsanger.gz
	SRR24312419_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

MYC family amplification dictates sensitivity to BET bromodomain protein inhibitor Mivebresib (ABBV-075) in small cell lung cancer

Project description:Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first line therapy readily, rapid relapse is inevitable with few treatment options in the second line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN, but not MYCL1 nor non-amplified MYC cell lines, exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor Mivebresib (ABBV-075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the anti-proliferative effects of mivebresib. Furthermore, the activity of mivebresib in SCLC cell lines occurs primarily through BRD2, rather than BRD4. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Our study suggests that chromatin landscapes could establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.

2024-07-31 | GSE230649 | GEO

MYC family amplification dictates sensitivity to BET bromodomain protein inhibitor Mivebresib (ABBV-075) in small-cell lung cancer.

Project description:Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN, but not MYCL1 nor non-amplified MYC cell lines, exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor Mivebresib (ABBV-075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the anti-proliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes could establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.

| S-EPMC11294817 | biostudies-literature

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

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

Expression profile of 22Rv1 cells with GFP or HNF4G exogenous expression when treated with BETi ABBV-075

Project description:To study the consequence of HNF4G target genes expression with ABBV-075 treatment in cells that have BETi-independent HNF4G expression, we performed RNA-Seq on 22Rv1 cells that exogenously express HNF4G using GFP expression as control.

2025-01-18 | GSE254733 | 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

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

BET inhibitor ABBV-075 perturbed pathways in prostate cancer organoid MSK-PCa17

Project description:BET inhibitor ABBV-075 perturbed pathways in prostate cancer organoid MSK-PCa17

| PRJNA1072115 | ENA

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

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