Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer

ABSTRACT: Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer

PROVIDER: PRJNA995781 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR25308650.fastq.gz	Fastqsanger.gz
	SRR25308651.fastq.gz	Fastqsanger.gz

Items per page:

1 - 2 of 2

Similar Datasets

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer

Project description:Keap1 mutant lung tumors were injected into mice and once lung tumors formed the mice were treated with anti-PD1, DRP-104, or the combination of the drugs. Immune cells and tumor cells were isolated from the lungs and ExCITE-seq was performed.

2024-04-03 | GSE237592 | GEO

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in <i>KEAP1</i> mutant lung cancer.

Project description:Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

| S-EPMC10971495 | biostudies-literature

Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade [scRNA-seq]

Project description:Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.

2023-02-24 | GSE218429 | GEO

Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade [scBisulfite-seq]

2023-02-24 | GSE218423 | GEO

Glutamine antagonist JHU083 reprograms immunosuppressive tumor-associated macrophages to drive tumor immunity in urologic cancers, bulk RNA-seq

Project description:Glutamine metabolism in the tumor microenvironment is emerging as a critical regulator of immune-mediated anti-tumor responses. We report potent tumor growth inhibition by the glutamine antagonist prodrug JHU083 in urologic tumors by JHU083-reprogrammed tumor-associated macrophages (TAMs) and tumor-infiltrating monocytes (TIMs). Using orthogonal approaches, we show that JHU083-mediated glutamine antagonism in the tumor microenvironment induces TNF, inflammatory, and mTORC1 signaling in different intra-tumoral TAM clusters. Additionally, we report that JHU083 increases proliferation in tissue-resident macrophages intratumorally and in different TAM sub-clusters. Functionally, we report that JHU083-reprogrammed TAMs have increased tumor cell phagocytosis and diminished pro-angiogenic capacities. In vivo inhibition of glutamine consumption in TAMs results in increased glycolysis, broken TCA cycle, and disruption in purine metabolism. Although the effect of glutamine antagonism was less profound on tumor-infiltrating T cells for their anti-tumor activity, it promoted a stem cell-like phenotype in CD8+ T cells and decreased the CD4+ Treg abundance. Additionally, we report that JHU083 causes a global shutdown in glutamine utilizing metabolic pathways in tumor cells, leading to reduced HIF-1, c-MYC phosphorylation, and induction of tumor cell apoptosis, all key anti-tumoral features.

2024-05-18 | GSE229222 | GEO

Combined with Gefitinib Overcomes Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer

Project description:Glutamine is a major energy source for tumor cells and blocking glutamine metabolism is being investigated as a promising strategy for cancer therapy. However, the antitumor effect of glutamine blockade in bladder cancer remains unclear, necessitating further investigation. Here, we demonstrated that glutamine metabolism was involved in the malignant progression of bladder cancer. Treatment with the glutamine antagonist 6-Diazo-5-oxo-L-norleucine (DON) inhibited bladder cancer cells in vitro in several ways. In addition, we observed a remarkable inhibition of tumor growth in bladder cancer-bearing mice using JHU083, a prodrug that was designed to prevent DON-induced toxicity. However, the antitumor immune effect of T cells changed from activation to inhibition as the administrated time extended. We found that both in vitro treatment with DON and in vivo prolonged administration of JHU083 led to the upregulation of PD-L1 in bladder cancer cells. Mechanistically, glutamine blockade up-regulates PD-L1 expression in bladder cancer cells by accumulating ROS, subsequently activating the EGFR/ERK/C-Jun signaling pathway. Combinatorial treatment with JHU083 and gefitinib reversed the up-regulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade. This reversal resulted in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings suggested that broad targeting of glutamine metabolism could represent a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.

2024-08-08 | GSE269520 | GEO

Glutamine antagonist JHU083 reprograms immunosuppressive tumor-associated macrophages to drive tumor immunity in urologic cancers, single-cell RNA-seq

2024-05-18 | GSE229223 | GEO

Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade

Project description:Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade

| PRJNA903816 | ENA

RNA-sequencing on sorted tumor-associated macrophages from vehicle or JHU083 pro-drug of 6-Diazo-5-oxo-L-norleucine (glutamine antagonist) treated 4T1 (breast cancer) tumor bearing mice

Project description:RNA-sequencing was performed on sorted tumor-associated macrophages (CD45+7AAD-CD11b+F4/80+CD8-Ly6C-Ly6G-) from 4T1 tumor (murine breast cancer) bearig mice with or without JHU083, pro-drug of 6-Diazo-5-oxo-L-norleucine (glutamine antagonist) treatment for expression profiling

2020-07-08 | GSE119733 | GEO

RNA-sequencing on sorted infiltrating CD8 T cells from vehicle or JHU083, pro-drug of 6-Diazo-5-oxo-L-norleucine (glutamine antagonist) treated MC38 (colon cancer) tumor bearing mice

Project description:RNA-sequencing was performed on sorted CD11b-CD11c-B220-CD45+TCRbeta+CD44+CD8+ TIL from vehicle or JHU083 treated MC38 tumor-bearing mice with or without JHU083, pro-drug of 6-Diazo-5-oxo-L-norleucine (glutamine antagonist) treatment for expression profiling

2020-02-24 | GSE120345 | 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