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Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma

ABSTRACT: Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma

PROVIDER: PRJNA807285 | ENA |

REPOSITORIES: ENA

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Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma

Project description:Targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation.

2023-11-27 | GSE196766 | GEO

Targeting DNA2 overcomes metabolic reprogramming in multiple myeloma.

Project description:DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.

| S-EPMC10853245 | biostudies-literature

SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma

Project description:SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma

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Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma

Project description:Transcriptional heterogeneity overcomes super-enhancer disrupting drug combinations in multiple myeloma

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Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

Project description:Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer

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Activation of the Integrated Stress Response by a Jumonji Histone Demethylase Inhibitor Induces Pro-Apoptotic Metabolic Reprogramming in Multiple Myeloma

Project description:Regulation of gene expression by chromatin modification through methylation of histone lysine residues is a dynamic, reversible process that when deregulated is associated with cancer development. In multiple myeloma, combined inhibition of the histone demethylases JARID1B, UTX and JmjD3 by the small molecule GSK-J4 prevents cellular glutamine utilization leading to amino acids deprivation, activates the integrated stress response via GCN2-dependent ATF4 activation, and induces apoptosis. This response is associated with a profound upregulation of metallothionein genes. Combined with clinical data demonstrating that overexpression of JARID1B is associated with shorter survival in multiple myeloma patients, this study highlights histone demethylases as epigenetic drug targets and places this demethylase inhibitor chemotype as having unique potential relative to established anti-myeloma treatment options. In total there are 7 different samples analyzed and one input control. Treatments are carried out with the demethylase inhibitor (or DMSO as negative control) at 6h and 48h, or with LNA targeting demethylases (or scrambled LNA) at 7 days. A negative control at 0h is included.

2015-08-21 | E-GEOD-60626 | biostudies-arrayexpress

SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma

Project description:SUMOylation, a posttranslational modification, regulates proteins by covalent attachment of small ubiquitin-like modifier (SUMO) proteins to a lysine (Lys) residue on target proteins. Here we use TAK-981, a selective SUMO-activating enzyme (SAE) inhibitor, to inhibit global SUMOylation in glucocorticoid sensitive and resistant multiple myeloma cell lines.

2021-12-31 | GSE163682 | GEO

Cancer-associated fibroblasts metabolic targeting overcomes T-cell exclusion and chemoresistance

Project description:Cancer-associated fibroblasts metabolic targeting overcomes T-cell exclusion and chemoresistance

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Nelfinavir overcomes proteasome inhibitor resistance in multiple myeloma by modulating lipid bilayer composition and fluidity

Project description:Nelfinavir has broad anti-cancer activity precilincally as a single agent and in combination. Clinically, it is particularly effective in the therapy of proteasome inhibitor-refractory multiple myeloma. The broad anti-cancer mechanism of action of nelfinavir implies that it may interfere with very fundamental aspects of cancer cell biology. We combined proteome-wide affinity-purification with genome-wide CRISPR/Cas9-based screening to identify protein partners interacting with nelfinavir alongside with candidate genetic contributors affecting nelfinavir cytotoxicity. We show that nelfinavir has multiple binding partners embedded in organellar lipid-rich membranes. By binding to these, nelfinavir affects the composition and fluidity of lipid-rich membranes, which subsequently disrupts downstream membrane-related processes, such as lipid metabolism, glucose processing, mitochondrial respiration, vesicular transport and ABCB1-mediated drug efflux. Targeting membrane fluidity by FDA-approved drug nelfinavir is a potent mechanism to achieve anti-cancer activity and is in particular suitable for the treatment of proteasome inhibitor-refractory multiple myeloma.

2021-11-02 | PXD023260 | Pride

Multiple myeloma

Project description:Multiple myeloma

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