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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

ABSTRACT: Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

PROVIDER: PRJNA625333 | ENA |

REPOSITORIES: ENA

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Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

Project description:By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including Imipramine, induced cancer cell death in combination with the mitochondrial uncoupler Niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors Chop and TFE3, which resulted in cell death damage through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy Paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.

2021-01-21 | GSE148682 | GEO

Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism.

Project description: Not available

| S-EPMC8033521 | biostudies-literature

Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

Project description: Not available

| S-SCDT-EMM-2020-12461 | biostudies-other

Figure 2 "Small Molecule Inhibitors of Complex IV Induce Cell Death through Imbalanced Pyrimidine Expansion"

Project description:Basal and B508 treated TMT-labeled 10-plex whole proteomes from resistant and sensitive cell lines. Associated with Figure 2 from "Small Molecule Inhibitors of Complex IV Induce Cell Death through Imbalanced Pyrimidine Expansion".

2022-06-10 | MSV000089626 | MassIVE

A Pyrazolo[3,4-d]Pyrimidine compound (a Fyn inhibitor) induces apoptosis and cell death in Large Granular Lymphocyte Leukemia cells

Project description:KHYG1 cell line (NK leukemia) were treated with a new compound, a pyrazolo[3,4-d]Pyrimidine. This compound induces apoptosis and cell death in this cell line. The mechanisms of apoptosis and cell death were investigated. A gene expression profile was used as support.

2016-10-03 | E-MTAB-4536 | biostudies-arrayexpress

Identification of clinical combination therapies to induce durable responses in kidney cancers

Project description:Identification of clinical combination therapies to induce durable responses in kidney cancers

| PRJNA719177 | ENA

Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death.

Project description: Not available

| S-EPMC5094989 | biostudies-literature

KMT2A oncoproteins induce epigenetic resistance to targeted therapies.

Project description:KMT2A oncoproteins induce epigenetic resistance to targeted therapies.

| PRJNA1060315 | ENA

Targeting Pyrimidine Synthesis Accentuates Molecular Therapy Response in Glioblastoma Stem Cells

Project description:Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamyolase, dihydroorotase) or the critical downstream enzyme, DHODH (dihydroorotate dehydrogenase) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity. Higher expression of pyrimidine synthesis genes portend poor prognosis of glioblastoma patients. Collectively, our results demonstrate a novel therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

2019-04-09 | GSE129438 | GEO

Cellular pyrimidine imbalance triggers mitochondrial DNA-dependent innate immunity [HeLa_CAD_RNA-seq]

Project description:Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP–AMP syn- thase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS–STING–TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflamma- tion in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS–STING–TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.

2021-02-26 | GSE161733 | GEO

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