Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

ABSTRACT: Acquired resistance to tyrosine kinase inhibitors, such as Osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-mutational mechanisms. Here, we generate and comprehensively characterize the chromatin accessibility and gene regulatory signatures of pairs of parental and Osimertinib-resistant EGFR-mutant cell lines. Specifically, we profile the genome-wide localization of mSWI/SNF chromatin remodeling complexes in these cell line pairs, identifying both pan-cell and tumor cell-specific gene targets underlying the resistance state. Importantly, genetic and small molecule-based pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant cell lines and in vivo tumor models to Osimertinib. This re-sensitization is linked to mSWI/SNF-mediated regulation of cell proliferative, epithelial to mesenchymal transition, and epithelial cell differentiation-related programs, as well as NRF2 signaling. These data highlight the role for mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227999 | GEO | 2023/09/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

Project description:Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.

2023-08-03 | GSE202859 | GEO

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

2023-08-03 | GSE202857 | GEO

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

2023-08-03 | GSE202864 | GEO

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer

2023-08-03 | GSE202863 | GEO

MUSASHI-2 RNA binding protein confers resistance to an epidermal growth factor receptor-tyrosine kinase inhibitor Osimertinib in lung adenocarcinoma

Project description:Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the acquired resistance to EGFR-TKIs, even third generation Osimertinib, the patients suffer poor prognosis. The resistance mechanisms are still not fully understood. Here, we demonstrate that increased expression of MUSASHI-2 (MSI2), an RNA binding protein, is novel mechanisms for resistance to EGFR-TKIs. We found that after long-exposure of gefitinib, the first generation EGFR-TKI, lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to not only gefitinib but also Osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the top list of the stemness-related genes upregulated in the EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including expression levels of Nanog a core stemness factor. We demonstrate that knockdown of MSI2 restored sensitivity to Osimertinib or gefitinib in the EGFR-TKI-resistant cells to the similar levels of the parental cells in vitro. RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to Osimertinib or gefitinib in parental cells. Finally, knockdown of MSI2 greatly increased sensitivity to Osimertinib in vivo. Collectively, our findings provide proof-of-principle that targeting MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent emergence of acquired resistance.

2021-08-27 | GSE168280 | GEO

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [RNA-seq]

Project description:Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. Whilst patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq, ChIP-seq, and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic opportunities.

2022-04-06 | GSE193258 | GEO

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ChIP-seq]

2022-04-06 | GSE193257 | GEO

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ATAC-seq]

2022-04-06 | GSE193256 | GEO

Gene expression data in the human non-small cell lung cancer cell line NCI-H1975 and osimertinib-resistant OR1 and OR2 cells

Project description:Osimertinib, a third-generation EGFR-TKI, has applied to non-small cell lung cancer harboring activated EGFR mutation with or without T790M. However, the appearance of tumors resistant to osimertinib has been reported. We established and characterized osimertinib-resistant cells derived from NCI-H1975 cells harboring activating EGFR and T790M mutation.

2022-04-28 | GSE201608 | GEO

The differential gene expression of the lung cancer cell line HCC827 before and after resistance to osimertinib

Project description:Osimertinib, as a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been approved as a first-line therapy in advanced non–small-cell lung cancer (NSCLC) patients with EGFR-activating or T790M resistance mutations. However, the efficacy of osimertinib is limited due to acquired resistance. In order to search for the mechanism of resistance to osimertinib, we screened on significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells via RNA-sequence.In summary, our data elucidate the alterations in gene expression within lung cancer cells before and after resistance to osimertinib, aiding in the analysis and identification of key molecules influencing osimertinib resistance.

2024-03-30 | GSE262582 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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