Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA263564 | ENA |
REPOSITORIES: ENA
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Project description:Modulation of the activity of the ubiquitin-proteasome pathway with the proteasome inhibitor (PI) is an established component of therapy for plasma cell disorders. However, resistance emerges and the mechanism is incompletely understood. We generated carfilzomib-resistant (CR) myeloma cell lines by exposing drug-naive ANBL-6, KAS-6/1, U266, and OPM-2 cells to increasing concentrations of carfilzomib and then performed gene expression profiling (GEP) to identify prominent changes compared to their vehicle-treated counterparts, followed by exploration of the mechanism(s) of proteasome inhibitor resistance.
2016-10-09 | GSE62237 | GEO
Project description:RNA was extracted from myeloma cell lines that were either drug-naïve or resistant to bortezomib or carfilzomib and the transcriptome was characterised using RNA sequencing.
2021-12-01 | GSE144249 | GEO
Project description:Ubiquitin proteasome expression in Mulitple Myeloma cell lines
| PRJNA314296 | ENA
Project description:Comparison of the gene expression profiles of carfilzomib-resistant derivatives versus parental human myeloma cell lines
| PRJNA284490 | ENA
Project description:Transcriptomic profiling of drug-naïve or proteasome inhibitor-resistant myeloma cell lines
| PRJNA603122 | ENA
Project description:The use of proteasome inhibitors (PIs) is the backbone of multiple myeloma (MM) treatment. However, almost all MM patients who initially respond to PIs eventually develop resistance to these drugs. The discovery of a pharmacological intervention that increase the potency of PIs in order to reduce their dose and/or restore the sensitivity of MM cells to PIs is an important avenue in MM research. Insulin Degrading Enzyme (IDE) is a druggable protease known to modulate proteasome. We show here that, in two independent cohorts, a high expression of IDE in cells from MM patients is associated with shorter overall survival. Likewise, we designed specific, cell permeable, IDE inihibitors and showed that full pharmacological engagement of IDE is associated with enhanced sensitivity to PIs of MM cell lines, as well as of primary patient MM cells. Furthermore, treatment of PI-resistant MM cells with the inhibitor overcomes their resistance to PI. Finally we designed an improved IDE inhibitor suitable for in vivo pharmacology. This inhibitor which develops multiple interactions with IDE at the catalytic site and display good pharmacocinetic properties, boosts the anti-myeloma potency of bortezomib in a syngenic mouse model of MM. In vitro, it appears that IDE inhibition reduces the residual proteasome activty in PI-treated cells and increases the apoptotic potency of carfilzomib through induction of an Integrated Stress Response associated with strongly reduced IGF1 and IGF1R expressions. The pharmacological profile of this new combination appears highly desirable for the treatment of MM.
2024-09-15 | GSE184310 | GEO
Project description:Bortezomib (BTZ), Carfilzomib (CFZ) and Ixazomib (IXA) are proteasome inhibitors (PI) approved for Multiple Myeloma (MM) treatment. By design, they all target the rate-limiting proteasome beta 5 (B5) subunit. CFZ treatment increases the survival of patients with relapsed/refractory MM compared to BTZ but is associated with heart failure not commonly observed for BTZ. The molecular basis for CFZ-induced cardiotoxicity is poorly understood. We time to investigate the transcriptomic effects of acute proteasome inhibition in the murine heart.
2023-07-01 | E-MTAB-11028 | biostudies-arrayexpress
Project description:Multiple Myeloma patients were treated with the proteasome inhibitor carfilzomib in different protocols according to their clinical stage. Paired serum samples were obtained before i.v injection and after 1-8h post treatment and snap frozen. Samples were stored at -80°C until analysis.
2021-09-21 | ST001925 | MetabolomicsWorkbench
Project description:Relapsed/refractory multiple myeloma (r/r MM) is a disease with often poor prognosis. Hyperactive SUMO signaling is involved in both cancer pathogenesis and cancer progression. A state of increased SUMOylation has been associated with aggressive cancer biology. Here, we found that r/r MM is characterized by a SUMO-high state, and high expression of SUMO E1 ligase (SAE1/UBA2) was associated with poor overall survival. Induced resistance to the second generation proteasome inhibitor (PI) carfilzomib (CFZ) enhanced SUMO pathway activity. Accordingly, CFZ-pretreated patients showed enhanced SUMO pathway activity in the MM compartment. Treatment of MM cell lines with subasumstat, a novel small-molecule SUMO E1 activating enzyme inhibitor, showed synergistic treatment efficacy with CFZ in both PI-sensitive and PI-resistant MM cell lines irrespective of the TP53 state. Combination therapy was effective in two murine MM xenograft models, where in vivo growth was significantly inhibited, and in patient-derived primary MM cells in vitro. Mechanistically, combined subasumstat and CFZ treatment enhanced DNA stress and apoptosis. In summary, our findings reveal activated SUMOylation as a therapeutic target in MM and point to combined SUMO/proteasome inhibition as a novel potent strategy for the treatment of patients with MM.
2022-08-01 | PXD032316 | Pride
Project description:Genome-wide analysis of gene expression in response to bortezomib treatment(33 nM) in cell lines before and after selection for resistance. Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. While the first-to-market proteasome inhibitor bortezomib/VELCADE has been successfully used to treat myeloma patients, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive and -resistant cell lines created from the Bcl-XL/Myc double transgenic mouse model of MM. Finally, these data reveal complex heterogeneity within MM and suggest resistance to one drug class reprograms resistant clones to make them more sensitive to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy of MM patients. Transcript profiling timecourses after treatment with Bortezomib treatment (33nm) in Multiple Myeloma derived cell lines.
2013-07-02 | E-GEOD-41928 | biostudies-arrayexpress