Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of Omaveloxolone as An Endoplasmic Reticulum Associated Degradation Inhibitor That Induces ER Stress and Early Apoptotic Signaling in Multiple Myeloma

ABSTRACT: Multiple myeloma (MM) is an incurable plasma cell neoplasm that is highly reliant on endoplasmic reticulum associated degradation (ERAD) to maintain protein homeostasis. Disrupting ERAD activity has been proposed to be preferentially cytotoxic to malignant plasma cells and may overcome proteasome inhibitor resistance, however, the identification of novel inhibitors has been limited. We developed a screening approach to identify ERAD modulators and applied it in the FDA repurposing library. Here we report a novel compound, omaveloxolone (RTA408), inhibits ERAD activity, rapidly induces the unfolded protein response, and leads to rapid induction of caspase 8 mediated apoptotic signaling in MM. Furthermore, we find that unlike proteasome inhibitors (PIs), RTA408 leads to sustained inhibition of ERAD protein degradation without affecting cytosolic protein degradation, which may address key mechanisms of PI resistance. Importantly we find that ERAD inhibition by RTA408 is cytotoxic in malignant plasma cells with PI resistance and has in vivo anti-myeloma activity. Altogether these studies provide pre-clinical evidence for application of a novel ERAD inhibitor in MM and highlight how it can be leveraged to study ER protein regulation in MM.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Multiple Myeloma

SUBMITTER: Erin Kropp

LAB HEAD: Qing Li1

PROVIDER: PXD061058 | Pride | 2026-03-09

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	PRF_A_2024_Q_LI_1239_68405_68422_1.raw	Raw
	PRF_A_2024_Q_LI_1239_68405_68422_10.raw	Raw
	PRF_A_2024_Q_LI_1239_68405_68422_11.raw	Raw
	PRF_A_2024_Q_LI_1239_68405_68422_12.raw	Raw
	PRF_A_2024_Q_LI_1239_68405_68422_1_12.msf	Msf

Items per page:

1 - 5 of 14

Similar Datasets

CRIP1 involves the pathogenesis of multiple myeloma via dual-regulation of proteasome and autophagy

Project description:Multiple myeloma (MM) is an incurable hematological malignancy of plasma cells. The maintenance of protein homeostasis is critical for the survival of MM cells. The excess paraprotein in MM cells undergoes clearance through proteasomes or lysosomes, two inter-connected yet independent pathways. While proteasome inhibitors (PIs) serve as fundamental agents significantly improving patient outcomes, heightened autophagy activity diminishes sensitivity to PI treatment.Elevated CRIP1 levels serve as a biomarker for relapsed/refractory MM and correlate with shorter overall patient survival. To further comprehend the role of CRIP1 in multiple myeloma pathogenesis, we conducted transcriptome sequencing.

2023-11-27 | GSE248339 | GEO

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma. We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerability in myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

2020-02-21 | PXD012172 | Pride

Proteasome inhibitor-induced modulation reveals the spliceosome as a specific therapeutic vulnerability in multiple myeloma

Project description:Resistance to proteasome inhibitors (PIs) is a ubiquitous clinical concern in multiple myeloma (MM). We proposed that signaling-level responses after PI would reveal new means to enhance efficacy. Unbiased phosphoproteomics after the PI carfilzomib surprisingly demonstrated the most prominent phosphorylation changes on spliceosome components. Spliceosome modulation was invisible to RNA or protein abundance alone. Transcriptome analysis demonstrated broad-scale intron retention suggestive of PI-specific splicing interference. Direct spliceosome inhibition synergized with carfilzomib and showed potent anti-myeloma activity. Functional genomics and exome sequencing further supported the spliceosome as a specific vulnerabilityin myeloma. Our results propose splicing interference as an unrecognized modality of PI mechanism, reveal additional modes of spliceosome modulation, and suggest spliceosome targeting as a promising therapeutic strategy in myeloma.

2020-02-18 | GSE124510 | GEO

Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma, dataset 2

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating this resistance, we mapped genetic co-dependencies associated with the proteasome. These studies identified cytosolic heat shock protein 70 (HSP70) chaperones as a potential target, mirroring recent studies that have shown mechanism of overcoming PI-induced stress. Here, we first underscore this relationship by mapping genetic co-dependencies in cancer proteostasis. These results lead us to explore HSP70 inhibitors as potential therapeutics. We show these compounds exhibit increased efficacy against both acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC proteomics reveal that JG’s overcome PI resistance not via the expected mechanism of inhibiting cytosolic HSP70s, but instead through mitochondrial-localized HSP70, HSPA9, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on response to PI. Our results characterize dynamics of myeloma proteostasis networks under therapeutic pressure while further motivating investigation of HSPA9 as a specific target in PI-resistant disease. This dataset corresponds to experiment outlined in figure 4a.

2020-04-24 | PXD018617 | Pride

Allosteric HSP70 inhibitors in Proteasome Inhibitor Resistant Multiple Myeloma

Project description:Proteasome inhibitor (PI) resistance remains a central challenge in multiple myeloma. To identify pathways mediating resistance, we first mapped proteasome-associated genetic co-dependencies. We identified cytosolic heat shock protein 70 (HSP70) chaperones as potential targets, consistent with proposed mechanisms of myeloma tumor cells overcoming PI-induced stress. These results led us to explore allosteric HSP70 inhibitors (JG compounds) as myeloma therapeutics. We showed these compounds exhibit increased efficacy against acquired and intrinsic PI-resistant myeloma models, unlike HSP90 inhibition. Surprisingly, shotgun and pulsed-SILAC mass spectrometry found that JGs have the most pronounced effect on the proteome not through inhibiting cytosolic HSP70s but instead through mitochondrial-localized HSP70, HSPA9/mortalin, destabilizing the 55S mitoribosome. Analysis of myeloma patient data further supports strong effects of global proteostasis capacity, and particularly HSPA9 expression, on PI response. Our results characterize myeloma proteostasis networks under therapeutic pressure while motivating further investigation of HSPA9 as a specific vulnerability in PI-resistant disease.

2022-05-27 | PXD032030 | Pride

Hepatic Sel1L-Hrd1 ER-associated degradation deficiency leads to intrahepatic cholestasis in mice

Project description:The liver is the central organ critically regulating the balance of the metabolically potent yet toxic bile acids in the body. While genomic association studies have pointed to hepatic Sel1L – a critical component of mammalian Hrd1 ER-associated degradation (ERAD) machinery – as an influencer of serum bile acid levels, physiological relevance and mechanistic insights of ERAD in bile homeostasis remain unexplored. Using hepatocyte-specific Sel1L-deficient mouse models, we report that hepatic Sel1L-Hrd1 ERAD critically manages bile homeostasis in the body. Mice with hepatocyte-specific Sel1L developed intrahepatic cholestasis, with significant overload of bile acids in the liver and circulation under basal condition, and were hypersensitive to dietary bile acid challenge. By contrast, biliary bile acid and phosphatidylcholine levels were reduced, pointing to an export defect from hepatocytes. Unbiased proteomics analysis followed by biochemical assays revealed significant accumulation of the bile-stabilizing phosphatidylcholine exporter ATP-binding cassette 4 (Abcb4) in the ER of Sel1L-deficient livers, a gene associated with Progressive Familial Intrahepatic Cholestasis type III. Indeed, Abcb4 was a substrate of Sel1L-Hrd1 ERAD. Hence, hepatic Sel1L-Hrd1 ERAD maintains bile equilibrium via quality control of Abcb4 maturation in the ER.

2023-03-11 | PXD035243 | Pride

Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

2020-04-24 | PXD018387 | Pride

Clinical drug resistance linked to reversible phenotypic transition and epigenetic alteration in multiple myeloma

Project description:The development of proteasome inhibitors (PIs) for the treatment of multiple myeloma (MM) has dramatically increased treatment responses and improved survival. The first-in-class PI, bortezomib, was used in a twice-weekly intravenous as a sustained single or combinational regimen for relapsed and subsequently for newly diagnosed MM. The relatively rapid acquisition of drug resistance to PI treatment remains a crucial obstacle. Gradual familiarity with toxicity and optimizing dose schedules have formed the current use of PIs as key components in promoting response and eliminating resistance. Combination therapies and schedule adaptation to once-weekly use of PIs have meanwhile been shown to be both more tolerable and highly efficacious. Interestingly, patients may remain sensitive to PIs after relapse of initial therapy, implying that PI resistance is reversible and suggest a previously unrecognized drug resistance mechanism via epigenetic changes that may be intrinsic to PI treatment.

2021-02-24 | GSE136725 | GEO

Synergistic efficacy of combined SUMOylation and proteasome inhibition in multiple myeloma

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

Synthetic IDE inhibitors sensitize and reverse acquired resistance of multiple myeloma cells to proteasome inhibitors

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data