Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MYC couples SWI/SNF and metabolic reprogramming to sustain minimal residual disease in mTORC1-activated cancer cells [WES]

ABSTRACT: Therapeutics blocking PI3K-mTORC1 are commonly used for tumor treatment, and at times achieve major responses, yet minimal residual disease (MRD) persists, leading to tumor relapse. We examined the MRD models established both in vitro (Rapamycin persistent, RP) and in vivo after mTORC1 inhibition. All RP/MRD cell lines showed complete growth and signaling insensitivity to rapamycin but variable sensitivity to bi-steric mTORC1 inhibitors. MTORS2035 mutations were identified in 4 of 7 RP cell lines. Multi-omic analysis identified a pronounced shift to oxidative phosphorylation and away from glycolysis in all RP/MRD models, with increased mitochondrial number and function. MYC and SWI/SNF expression were greatly enhanced. Both the SWI/SNF inhibitor AU-15330 and the Complex I inhibitor of oxidative phosphorylation IACS-010759 showed pronounced synergy with bi-steric mTORC1 inhibitors to cause cuproptotic cell death in RP/MRD cells, suggesting these combinations as a potential patient treatment strategy for rapalog resistance.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE270778 | GEO | 2025/06/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

MYC couples SWI/SNF and metabolic reprogramming to sustain minimal residual disease in mTORC1-activated cancer cells [RNA-seq]

Project description:Therapeutics blocking PI3K-mTORC1 are commonly used for tumor treatment, and at times achieve major responses, yet minimal residual disease (MRD) persists, leading to tumor relapse. We examined the MRD models established both in vitro (Rapamycin persistent, RP) and in vivo after mTORC1 inhibition. All RP/MRD cell lines showed complete growth and signaling insensitivity to rapamycin but variable sensitivity to bi-steric mTORC1 inhibitors. MTORS2035 mutations were identified in 4 of 7 RP cell lines. Multi-omic analysis identified a pronounced shift to oxidative phosphorylation and away from glycolysis in all RP/MRD models, with increased mitochondrial number and function. MYC and SWI/SNF expression were greatly enhanced. Both the SWI/SNF inhibitor AU-15330 and the Complex I inhibitor of oxidative phosphorylation IACS-010759 showed pronounced synergy with bi-steric mTORC1 inhibitors to cause cuproptotic cell death in RP/MRD cells, suggesting these combinations as a potential patient treatment strategy for rapalog resistance.

2025-06-10 | GSE270777 | GEO

MYC couples SWI/SNF and metabolic reprogramming to sustain minimal residual disease in mTORC1-activated cancer cells [CUT&RUN, ATAC-seq]

2025-06-10 | GSE270774 | GEO

Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1

Project description:The PI3K-AKT-mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit likely due to their lack of effects on 4E-BP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multi-omic analysis showed extensive effects of the bi-steric inhibitors in comparison to rapamycin. De novo purine synthesis was markedly and selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a novel therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.

2023-11-08 | GSE236742 | GEO

Selective Inhibitors of mTORC1 Activate 4EBP1 and Suppress Tumor Growth

Project description:The clinical benefit of current mTOR inhibitors is limited, perhaps reflecting their intrinsic pharmacological profiles. Rapamycin analogs selectively inhibit mTORC1, but fail to suppress phosphorylation of the mTORC1 substrate 4EBP1, a translational repressor that is a key driver of oncogenic mTORC1 signaling. mTOR kinase active-site inhibitors fully suppress mTORC1 and phosphorylation of its substrates, but are active against mTORC2 and additional kinases, potentially contributing to tolerability limitations. The prototype bi-steric inhibitor RapaLink-1 exploits the selective mTORC1 interactions of rapamycin and the broad mTOR kinase inhibitory effects of an active-site inhibitor, through covalent linkage of the two pharmacophores to achieve complete mTORC1/2 inhibition. We demonstrate that the anti-proliferative activity of RapaLink-1 is dependent upon mTORC1 and suppression of 4EBP1 phosphorylation. Using a rational design strategy, we tuned the affinities of the rapamycin core and ATP-mimetic moieties to create novel bi-steric inhibitors with enhanced mTORC1 selectivity and potency against 4EBP1 phosphorylation. mTORC1-selective bi-steric compounds produced durable inhibition of 4EBP1 phosphorylation in vitro and in vivo, and drove tumor regressions at well-tolerated doses in xenograft models of breast cancer.

2021-04-05 | GSE138417 | GEO

A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer

Project description:Activation of the PI3K-mTOR pathway is central to breast cancer pathogenesis including resistance to many targeted therapies. The mTOR kinase forms two distinct complexes, mTORC1 and mTORC2, and understanding which is required for the survival of malignant cells has been limited by tools to selectively and completely impair either subcomplex. To address this, we used RMC-6272, a bi-steric molecule with a rapamycin-like moiety linked to an mTOR active-site inhibitor that displays >25-fold selectivity for mTORC1 over mTORC2 substrates. Complete suppression of mTORC1 by RMC-6272 causes apoptosis in ER+/HER2- breast cancer cell lines, particularly in those that harbor mutations in PIK3CA or PTEN, due to inhibition of the rapamycin resistant, mTORC1 substrate 4EBP1 and reduction of the pro-survival protein MCL1. RMC-6272 reduced translation of ribosomal mRNAs, MYC target genes, and components of the CDK4/6 pathway, suggesting enhanced impairment of oncogenic pathways compared to the partial mTORC1 inhibitor everolimus. RMC-6272 maintained efficacy in hormone therapy-resistant acquired cell lines and patient derived xenografts (PDX), showed increased efficacy in CDK4/6 inhibitor treated acquired resistant cell lines versus their parental counterparts, and was efficacious in a PDX from a patient experiencing resistance to CDK4/6 inhibition. Bi-steric mTORC1-selective inhibition may be effective in overcoming multiple forms of therapy-resistance in ER+ breast cancers.

2024-06-01 | GSE230627 | GEO

Targeting SWI/SNF ATPases in H3.3K27M Diffuse Intrinsic Pontine Gliomas [ATAC-Seq]

Project description:Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), bearing lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are lethal childhood brain cancers. These tumors harbor a global reduction in the transcriptional repressive mark H3K27me3 accompanied by an increase in the transcriptional activation mark H3K27ac. We postulated that H3K27M mutations, in addition to altering H3K27 modifications, reprogram the master chromatin remodeling SWI/SNF complex. The SWI/SNF complex can exist in two main forms termed BAF and PBAF that play central roles in neurodevelopment and cancer. Moreover, BAF antagonizes PRC2, the main enzyme catalyzing H3K27me3. We demonstrate that H3K27M gliomas show increased protein levels of the SWI/SNF complex ATPase subunits SMARCA4 and SMARCA2 and the PBAF component PBRM1. Additionally, knockdown of mutant H3K27M lowered SMARCA4 protein levels. The proteolysis targeting chimera (PROTAC) AU-15330 that simultaneously targets SMARCA4, SMARCA2, and PBRM1 for degradation exhibits cytotoxicity in H3.3K27M but not H3 wild-type cells. AU-15330 lowered chromatin accessibility measured by ATAC-seq at non-promoter regions and reduced global H3K27ac levels. Integrated analysis of gene expression, proteomics, and chromatin accessibility in AU-15330-treated cells demonstrated reduction in levels of FOXO1, a key member of the forkhead family of transcription factors. Moreover, genetic or pharmacologic targeting of FOXO1 resulted in cell death in H3K27M cells. Overall, our results suggest that H3K27M upregulates SMARCA4 levels and combined targeting of SWI/SNF ATPases in H3.3K27M can serve as a potent therapeutic strategy for these deadly childhood brain tumors.

2023-04-16 | GSE229453 | GEO

Targeting SWI/SNF ATPases in H3.3K27M Diffuse Intrinsic Pontine Gliomas [RNA-Seq]

2023-04-16 | GSE229452 | GEO

Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1

Project description:Bi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1

| PRJNA992119 | ENA

A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer

Project description:A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer

| PRJNA962031 | ENA

Chromatin profiling following SWI/SNF inhibition in neuroblastoma cells [ChIP-seq]

Project description:To assess the genome-wide effects of SWI/SNF activity in MYCN-amplified neuroblastoma cells, we performed ChIP-seq in IMR-32 cells treated with either DMSO or the SWI/SNF inhibitor BRM014. Pronounced loss of chromatin occupancy was observed for members of the neuroblastoma core regulatory circuitry within 1 hour.

2023-10-24 | GSE206310 | 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