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BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc- induced lymphoma cells

ABSTRACT: The aim of the project was to determine the expression profiles of murine Myc-driven lymphpma cells (Lambda-820) treated with vehicle (DMSO, 1:1000), a BET inhibitor (RVX2135), an ATR inhibitor (VE-821) or a combination of RVX2135 and VE-821. All experimnets were performed in presence of 10uM Q-VD-OPH to block apoptosis. Cells were harvested 24 h after treatment start.

ORGANISM(S): Mus musculus

PROVIDER: GSE74873 | GEO | 2015/12/18

SECONDARY ACCESSION(S): PRJNA301706

REPOSITORIES: GEO

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BET bromodomain inhibitors synergize with ATR inhibitors to induce DNA damage, apoptosis, senescence-associated secretory pathway and ER stress in Myc- induced lymphoma cells

Project description:The aim of the project was to determine the expression profiles of murine Myc-driven lymphpma cells (Lambda-820) treated with vehicle (DMSO, 1:1000), a BET inhibitor (RVX2135), an ATR inhibitor (VE-821) or a combination of RVX2135 and VE-821. All experimnets were performed in presence of 10uM Q-VD-OPH to block apoptosis. Cells were harvested 24 h after treatment start. 4 samples (DMSO, RVX2135, VE-821 or RVX2135/VE-821) in duplicates

2015-12-18 | E-GEOD-74873 | biostudies-arrayexpress

ATR-mediated Proteome Remodeling is a Major Determinant of Homologous Recombination Capacity in Cancer Cells

Project description:DMSO or 5uM ATR inhibitor(VE-821) were treated for 8 days on U2OS cells prior to anlaysis.

2018-07-17 | PXD010223 | Pride

BET bromodomain inhibitors synergize with ATR inhibitors in melanoma.

Project description:Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma.

| S-EPMC5596569 | biostudies-literature

Aldehyde dehydrogenase inhibitors promote DNA damage in ovarian cancer and synergize with ATM/ATR inhibitors.

Project description:Rationale: Aldehyde dehydrogenase (ALDH) enzymes are often upregulated in cancer cells and associated with therapeutic resistance. ALDH enzymes protect cells by metabolizing toxic aldehydes which can induce DNA double stand breaks (DSB). We recently identified a novel ALDH1A family inhibitor (ALDHi), 673A. We hypothesized that 673A, via inhibition of ALDH1A family members, could induce intracellular accumulation of genotoxic aldehydes to cause DSB and that ALDHi could synergize with inhibitors of the ATM and ATR, proteins which direct DSB repair. Methods: We used immunofluorescence to directly assess levels of the aldehyde 4-hydroxynonenal and comet assays to evaluate DSB. Western blot was used to evaluate activation of the DNA damage response pathways. Cell counts were performed in the presence of 673A and additional aldehydes or aldehyde scavengers. ALDH inhibition results were confirmed using ALDH1A3 CRISPR knockout. Synergy between 673A and ATM or ATR inhibitors was evaluated using the Chou-Talalay method and confirmed in vivo using cell line xenograft tumor studies. Results: The ALDHi 673A cellular accumulation of toxic aldehydes which induce DNA double strand breaks. This is exacerbated by addition of exogenous aldehydes such as vitamin-A (retinaldehyde) and ameliorated by aldehyde scavengers such as metformin and hydralazine. Importantly, ALDH1A3 knockout cells demonstrated increased sensitivity to ATM/ATR inhibitors. And, ALDHi synergized with inhibitors of ATM and ATR, master regulators of the DSB DNA damage response, both in vitro and in vivo. This synergy was evident in homologous recombination (HR) proficient cell lines. Conclusions: ALDHi can be used to induce DNA DSB in cancer cells and synergize with inhibitors the ATM/ATR pathway. Our data suggest a novel therapeutic approach to target HR proficient ovarian cancer cells.

| S-EPMC7914353 | biostudies-literature

Chemical Inhibitors of a Selective SWI/SNF Function Synergize with ATR Inhibition in Cancer Cell Killing.

Project description:SWI/SNF (BAF) complexes are a diverse family of ATP-dependent chromatin remodelers produced by combinatorial assembly that are mutated in and thought to contribute to 20% of human cancers and a large number of neurologic diseases. The gene-activating functions of BAF complexes are essential for viability of many cell types, limiting the development of small molecule inhibitors. To circumvent the potential toxicity of SWI/SNF inhibition, we identified small molecules that inhibit the specific repressive function of these complexes but are relatively nontoxic and importantly synergize with ATR inhibitors in killing cancer cells. Our studies suggest an avenue for therapeutic enhancement of ATR/ATM inhibition and provide evidence for chemical synthetic lethality of BAF complexes as a therapeutic strategy in cancer.

| S-EPMC8273930 | biostudies-literature

MOLT-4 radiosensitization by VE-821

Project description:DNA damage induction by either radio- or chemo-therapy has been the most widely used approach in cancer therapy, exploiting the genomic instability of cancer cells. A promising strategy takes advantage of tumour specific abnormalities in DNA damage response. Inhibition of the ATR/Chk1 pathway has been shown to be synthetically lethal in cells with high levels of oncogene-induced replication stress and in p53- or ATM- deficient cells. In the presented study, we aimed to elucidate molecular mechanisms underlying radiosensitization of MOLT-4 cells by VE-821, a higly potent and specific inhibitor of ATR. We combined multiple approaches: cell biology techniques to reveal the inhibitor-induced phenotypes, and quantitative proteomics, phosphoproteomics, and metabolomics to comprehensively describe drug-induced changes in irradiated cells.

2018-07-16 | PXD008925 | Pride

Microarray analysis of HSVSMC treated with TGF-beta in the presence and absence of small molecule kinase inhibitors

Project description:Serum-starved, quieced HSVSMC (human saphenous vein smooth muscle cells, isolated from the great saphenous vein of coronary artery bypass graft patients) were treated with recombinant human TGFbeta-1 (10ng/mL) in the presence or absence of ALK5 kinase inhibitor SB-525334 (10uM) or ALK1/2 kinase inhibitor KO2288, https://doi.org/10.1371/journal.pone.0062721, (10uM). Gene expression analysis was performed on RNA extracted from cells at the 24h timepoint. RNA samples from three independent experiments (performed on cells from three different patients) were analysed. Quiesced, unstimulated cells were used as a negative control.

2019-08-16 | E-MTAB-7168 | biostudies-arrayexpress

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response

Project description:The DNA-damaging agent gemcitabine (GEM) is a first-line treatment for pancreatic cancer but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs including kinase inhibitors but the experimental evidence for such rational is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 140 clinical kinase inhibitors and observed strong synergy for the ATR inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway including phosphorylated pS468 of CHEK1 as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

2024-03-18 | MSV000094340 | MassIVE

Altering cancer transcriptomes using epigenomic inhibitors [Illumina beadchip]

Project description:We have compared the genome-wide effects on the transcriptome after treatment with ICG-001 (the specific CBP inhibitor) versus C646, a compound that competes with acetyl-coA for the Lys-coA binding pocket of both CBP and p300. We found that both drugs cause large-scale changes in the transcriptome of HCT116 colon cancer cells and PANC1 pancreatic cancer cells, and reverse some tumor-specific changes in gene expression. Interestingly, although the epigenetic inhibitors affect cell cycle pathways in both the colon and pancreatic cancer cell lines, the WNT signaling pathway was affected only in the colon cancer cells. Notably, WNT target genes were similarly down-regulated after treatment of HCT116 with C646 as with ICG-001. Total RNA obtained from isolated HCT116 or PANC1 cell lines were treated with 10uM ICG-001, 10uM C646, or 0.05% DMSO and collected after 12 or 96 hours.

2015-01-07 | E-GEOD-64038 | biostudies-arrayexpress

Quantitative proteomics of Giardia exposures to HKMT inhibitors

Project description:We explored differential protein expression (DEPs) during sublethal exposures of HKMT inhibitors (BIX-01294 = 10uM (B), Chaetocin = 20uM (C)) in log-phase (growth; TY) and encystation (differentiation; EC) at 8 and 24 hours relative to DMSO controls (D). In total, 18,527 peptides from 1,981 proteins in log-phase, and 19,852 peptides from 2,097 proteins were analysed in encysting cultures. In total, 56 proteins were up- and 36 down-regulated in log-phase trophozoites and 32 up- and 12 down during encystation upon BIX-01294-treatment relative to the DMSO controls. Following Chaetocin-treatment, 195 proteins were up- and 121 down-regulated in log-phase trophozoites, and 63 up- and 12 down during encystation. We have presented results by cell-phase given positive correlations were driven by culture condition and not between either Chaetocin or BIX-01294 inhibitor).

2020-08-04 | PXD016747 | Pride

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