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Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs.

ABSTRACT: We first treated senescent liver cancer cells with vehicle or ARV-825 for 48 hours. Then, RNA sequencing was conducted to quantify the mRNA expression level of vehicle-treated or ARV-825-treated liver cancer cells. ARV-825-induced expression changes were obtained based on the resultant data.

ORGANISM(S): Homo sapiens

PROVIDER: GSE233770 | GEO | 2026/01/01

REPOSITORIES: GEO

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Dual inhibition of CDK4/6 and XPO1 induced senescence with acquired vulnerability to CRBN-based PROTAC drugs

Project description:We treated liver cancer cells with vehicle, CDK4/6 inhibitor, XPO1 inhibitor and the combination. Then, RNA sequencing was conducted to quantify the mRNA expression level of vehicle-treated or CDK4/6 inhibitor, XPO1 inhibitor and the combination treated liver cancer cells. CDK4/6 inhibitor, XPO1 inhibitor and the combination induced expression changes were obtained based on the processed data.

2026-01-01 | GSE233531 | GEO

Effect of PROTAC-mediated BRD4 degradation on bone marrow-derived mesenchymal stromal cells [BM-MSCs]

Project description:BRD4, a member of the BET family of histone readers, binds to acetylated lysine of histone H3 and promotes assembly of super-enhancer complexes that drive expression of key oncogenes in acute myeloid leukemia (AML) and other cancers. ARV-825 is a proteolysis-targeting chimera (PROTAC) that targets BRD4 for CRBN-mediated ubiquitination and degradation. BM-MSCs are an important element of the bone marrow microenvironment of AML. To understand how targeting BRD4 in BM-MSCs may contribute to the overall effect on AML of targeting BRD4, we treated BM-MSCs from two normal donors with ARV-825 in vitro. Treatment of BM-MSC monocultures with ARV-825 for 24 hr caused extensive changes in gene expression, highly uniform between triplicates. Although the cultures from the two normal donors showed different profiles, their changes with ARV-825 were highly similar. These changes implicated effects on oxidative stress, osteogenic differentiation, retinoid metabolism, F-actin polymerization, CXCL12, and proliferation.

2019-10-01 | GSE101449 | GEO

Effect of PROTAC-mediated BRD4 degradation in acute myeloid leukemia [OCI-AML3]

Project description:BRD4, a member of the BET family of histone readers, binds to acetylated lysine of histone H3 and promotes assembly of super-enhancer complexes that drive expression of key oncogenes in acute myeloid leukemia (AML) and other cancers. ARV-825 is a proteolysis-targeting chimera (PROTAC) that targets BRD4 for CRBN-mediated ubiquitination and degradation. We treated the AML cell line OCI-AML3, as well as primary tumor cells from a case of AML, with ARV-825 in vitro. At low concentrations, ARV-825 caused profound and sustained reduction in BRD4 protein levels. This caused reduction in transcription of key genes including MYC, anti-apoptotic BCL2 and BCLXL, PIM1, and CD44. Downstream effects included loss of CXCR4 surface expression and mitochondrial respiration; increased reactive oxygen species; toxicity to AML cells in vitro; and efficacy vs. OCI-AML3 cells in a mouse model of AML.

2019-10-01 | GSE101380 | GEO

Novel BET protein Proteolysis Targeting Chimera (BET-PROTAC) exerts superior lethal activity than Bromodomain Inhibitor (BETi) against post-myeloproliferative Neoplasm (MPN) Secondary (s) AML Cells

Project description:The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Whereas the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reversed Phase Protein Array and mass cytometry ‘CyTOF’ analyses demonstrated that ARV-825 caused greater perturbations in mRNA and protein expressions than OTX015 in sAML cells. Specifically, compared to OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, pSTAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared to OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against the established and PD-CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

2017-04-06 | GSE93578 | GEO

BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against Mantle Cell Lymphoma cells

Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1, and the NFkB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the level of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared to ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Co-treatment of ARV-771 with ibrutinib or the BCL2-antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior pre-clinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or resistant MCL.

2019-04-26 | GSE98268 | GEO

RUNX1 knockdown and BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against mtRUNX1 AML cells

Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins which undermines the growth and survival of AML cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in AML cells. Unlike BETi, BET-PROTAC (proteolysis-targeting chimera) ARV-825 recruits and utilize an E3-ubiquitin ligase to effectively degrade BETPs in AML cells. BET-PROTACs induce more apoptosis than BETi of mtRUNX1 AML cells. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi. It was noted that treatment with BETi or BET-PROTAC caused significant and sustained depletion of RUNX1 in AML cells. We also determined the effects of global depletion of RUNX1 in mtRUNX1 expressing AML OCI-AML5 cells. We observed an overlap in the signature of RUNX1 knockdown by shRNA with that of OTX015 and ARV-825 in OCI-AML5 cells.

2020-08-11 | GSE119261 | GEO

LFQ of PROTAC-dependent biotinylated peptides in MM1.S cells expressing AirID-CRBN

Project description:MM1.S cells stably expressing AGIA-AirID-CRBN-WT were treated with DMSO, 1 µM pomalidomide, or 0.1 µM ARV-825 in the presence of 5 µM biotin and 5 µM MG132 for 6 h in three biological replicates. After tryptic digestion, biotinylated peptides were enriched with Tamavidin 2-REV and analyzed by LC-MS/MS.

2021-11-06 | PXD028763 | JPOST Repository

Analysis of genes of different expression in gastric cancer cells between ARV-825 treatment group and control group.

Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to analyze genes of different expression in gastric cancer cells between arv-825 treatment group and control group and to evaluate protocols for optimal high-throughput data analysis

2021-11-10 | GSE179581 | GEO

Transcriptome profiling of cardiomyocytes treated with antiretroviral drugs

Project description:The use of antiretroviral therapy (ART) improved the life expectancy of HIV patients through the suppression of HIV propagation in host. However, recent studies suggest that long-term use of ART induces comorbid conditions and heart failure in surviving HIV patients. The mechanism associated with the antiretroviral drugs (ARVs) induced cardiotoxicity and heart failure is not clear. In this study, we performed an RNA sequencing with ARV drugs-treated neonatal rat ventricular cardiomyocytes to explore drugs-induced cardiotoxicity. RNA-sequencing data analysis identified 1756 differentially expressed genes (padj<0.05) in cardiomyocytes. Out of 1756 genes, 701 genes were upregulated, and 1055 genes were downregulated in drug-treated cardiomyocytes. Functional enrichment analysis of differentially expressed genes was performed using clusterProfiler R and ingenuity pathway analysis. Our study showed that upregulated genes were linked with the biological processes associated with apoptosis, cellular movement or locomotion, cellular stress, and immune response. In contrast, down-regulated genes were involved in cell division and metabolism. Interestingly, we also found that ARV drugs treatment significantly upregulates the expression of a set of genes involved in cardiac enlargement and hypertrophy in the heart. Collectively, ARVs treatment in cardiomyocytes induces cardiotoxicity through differentially regulation of pathological genes expression in cardiomyocytes.

2021-12-29 | GSE188210 | GEO

ThBD-AGIA-AirID expressing MM1.S cells treated with DMSO, Pomalidomide or ARV-825

Project description:MM1.S cells stably expressing ThBD-AGIA-AirID were treated with DMSO, Pomalidomide or ARV-825 with MG132 in three biological replicates. Cell lysates were subjected to methanol-chloroform precipitation and digested with trypsin. Biotinylated peptides were purified by Tamavidin 2-REV and identified by LC-MS/MS analysis.

2025-09-03 | PXD067142 | JPOST Repository

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