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Targeting UHRF1: An Ixazomib Citrate Analogue as a Promising Therapeutic Agent for KRAS-Mutant Pancreatic Cancer

ABSTRACT: To investigate the effect of Ixazomib Citrate Analogue (ICA) inKRAS mutant on gene expression, we have emoloyed whole genomic microarray expression profiling using cancer cells

ORGANISM(S): Homo sapiens

PROVIDER: GSE325008 | GEO | 2026/05/30

REPOSITORIES: GEO

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Combinatorial Ixazomib and Belinostat Therapy Induce Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)-Dependent Apoptosis in Hodgkin and T-cell Lymphoma

Project description:Ixazomib has documented pre-clinical activity in T cell (TCL) and Hodgkin (HL) lymphoma models with transcriptomic analyses predicting synergistic activity in combination with histone deacetylase (HDAC) inhibition. In the present study, we determined the mechanistic basis for synergism with ixazomib in combination with the HDAC inhibitor, belinostat, in HL and TCL cells lines (ixazomib-sensitive and -resistant clones) and primary tumor cells. In ixazomib-treated TCL and HL cells, we observed induction of proteasomal gene expression and NRF2 as a prominent upstream regulator. Ixazomib treatment in TCL and HL cells resulted in transient inhibition followed by full recovery of proteasomal activity within 72 hours. Furthermore, transcriptomic analysis following belinostat treatment resulted in downregulation of both NRF2 and proteasomal gene expression (validated by qPCR) without direct impact on proteasomal activity in Jurkat and L428. In addition, CRISPR/Cas9 mediated knockdown of NRF2 in Jurkat cells resulted in a significant decrease in cell viability with ixazomib compared with untreated control cells. Using transcriptomic and proteosomal activity evaluation of ixazomib, belinostat or ixazomib+belinostat treated cells, we observed that NRF-2, proteasome gene expression and functional recovery were abrogated by the combination. We also confirmed that ixazomib/belinostat resulted in synergistic activity in ixazomib-sensitive and -resistant cell lines and primary cells. Altogether, these results suggest that the synergistic activity of ixazomib and belinostat is mediated via inhibition NRF2-dependent proteasomal recovery and extended proteasomal inhibition culminating in increased cell death. Further investigation is warranted to determine the full biological role for NRF2 as a response modifier in proteasomal targeted therapies.

2019-04-01 | GSE126768 | GEO

The role of UHRF1 in KRAS-mutated pancreatic cancer cells

Project description:To investigate the effect of UHRF1 in KRAS mutant on gene expression, we have emoloyed whole genomic microarray expression profiling using PL5 cells

2026-04-30 | GSE325201 | GEO

Phase II Trial of Ixazomib combined with Gemcitabine and Doxorubicin in Patients with SMARCB1-Deficient Renal Medullary Carcinoma

Project description:SMARCB1-deficient renal medullary carcinoma (RMC) is an aggressive kidney cancer lacking mechanism-directed therapies. We conducted a single-center, single-arm, phase II study (NCT03587662) testing the oral proteasome inhibitor ixazomib combined with gemcitabine and doxorubicin. Thirty consecutive patients (median age 34.5 years old, 90% Black, 83.3% metastatic at diagnosis) were treated between September 2018 and June 2022. Ixazomib 5.5 mg, gemcitabine 756 mg/m² and doxorubicin 42 mg/m² were given every 2 weeks for up to 13 cycles, followed by ixazomib plus gemcitabine maintenance. Co-primary endpoints were objective response rate (ORR) and 28-week disease-control rate (DCR) versus historical gemcitabine plus doxorubicin controls. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The posterior ORR was 36% (95% credible interval [CrI], 21–54 %) with a 91.4% probability of exceeding historical doublet therapy. However, the 28-week DCR was 17 % (95% CrI 6–31%), crossing the predefined futility boundary. Median PFS and OS were 3.5 months (95% confidence intervals [CI] 1.9–4.9) and 7.4 months (95% CI 2.1-4.9), respectively. Grade ≥ 3 toxicities were predominantly hematologic (thrombocytopenia 20 %, leukopenia 17%) and manageable. No treatment-related deaths occurred. Single-cell and bulk multi-omics from 11 patients revealed that immune-inflamed tumors enriched for T/NK cells, plasmacytoid and conventional dendritic cells, and S100A8/IL-1ß-skewed monocytes correlated with response, whereas stromal-myeloid niches and proliferative or neuroendocrine-squamous plastic epithelial states were associated with resistance. Resistant lesions upregulated unfolded-protein-response and Hippo pathways. These results pave the way for future biomarker-guided patient selection and rational combination or microenvironment-targeted therapies.

2026-01-13 | GSE306473 | GEO

Effects of strigolactone analogue dGR24 on the transcriptome of Bacillus subtillis

Project description:Objective: to compare and contrast the effects of exogenous application of strigolatone analogue rac-dGR24, on gene expression in bacillus subtilis. The experiment compared the effects on three genotypes: wild type and two mutant lines, a ∆rsbQ and RsbQS96A.

2023-12-06 | GSE236759 | GEO

iTRAQ analysis of immortalized mouse Schwann cells treated with Ixazomib

Project description:To determine differentially expressed proteins upon treatment with proteasome inhibitor, Ixazomib, in cultured mouse Schwann cells

2022-09-24 | PXD036003 | JPOST Repository

MYC and CHK1 Dependent Cell Death in T-cell Lymphoma and Hodgkin Lymphoma Cell Lines and Human Xenograft Models Via Anti-Proteasomal Therapy (Affymetrix)

Project description:We examined the biological effects of a potent second-generation proteasome inhibitor, ixazomib, in T-cell lymphoma and Hodgkin lymphoma cell lines and human xenograft models. Ixazomib resulted in time- and dose-dependent cytotoxicity and apoptosis in all cell lines (IC50’s <75nM). In vivo studies via SCID tumor xenografts showed significant inhibition of tumor growth (P<0.001) with significantly improved survival (P<0.001) in Jurkat and L540 models with ixazomib-treated mice versus controls. Through global transcriptome and network analyses, ixazomib-treated Jurkat and L540 cells showed significant overlap in biological functions involved in regulation of cell cycle, chromatin modification, and DNA repair processes with a lack of conservation observed in a relatively ixazomib-resistant cell line, L428. Moreover, the predicted activation and inhibition status of tumor suppressors and oncogenes strongly favored ixazomib inhibition of tumor progression. Most notably, ixazomib down-regulated protein levels of MYC and its target genes. Additionally, chromatin immunoprecipitation showed that histone H3 acetylation affected MYC levels and cell death response to ixazomib. Furthermore, inhibition of MYC with JQ1 resulted in synergistic cell death in L428, which was confirmed utilizing MYC knockout. Collectively, ixazomib down-regulated MYC and downstream substrates in TCL and HL, while resistance appeared mediated through MYC- and CHK1-dependent mechanisms.

2015-06-08 | GSE66417 | GEO

MYC and CHK1 Dependent Cell Death in T-cell Lymphoma and Hodgkin Lymphoma Cell Lines and Human Xenograft Models Via Anti-Proteasomal Therapy (Illumina)

2015-06-08 | GSE66415 | GEO

Citrate as Cost-Efficient NADPH Regenerating Agent.

Project description: Not available

| S-EPMC6315136 | biostudies-literature

Parsing digital or analogue TCR performance through piconewton forces

Project description:Parsing digital or analogue TCR performance through piconewton forces

| PRJNA1003535 | ENA

RNA-seq of kidneys from mice treated for eight weeks with the glucagon analogue, NNC9204-0043, compared to mice treated with PBS

Project description:Chronic glucagon receptor activation induced by a long-acting glucagon analogue causes thickening of the parietal layer of Bowman’s capsule, causes mesangial area expansion, and formation of albuminuria. To dissect the molecular mechanism underlying these effects, RNA sequencing of kidney biopsies from female mice treated for eight weeks with either the long-acting glucagon analogue, NNC9204-0043, or PBS were performed

2023-12-01 | E-MTAB-12520 | biostudies-arrayexpress

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