Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A-to-I edited miR-411-5p targets MET and promotes TKI response in NSCLC-resistant cells

ABSTRACT: Non-small cell lung cancer (NSCLC) patients carrying an epidermal growth factor receptor (EGFR) mutation have an initial favorable clinical response to the tyrosine kinase inhibitors (TKIs). Unfortunately, rapid resistance occurs mainly because of genetic alterations, including amplification of the hepatocyte growth factor receptor (MET) and its abnormal activity. The RNA post-transcriptional modifications that contribute to aberrant expression of MET in cancer are largely under-investigated and among them is the adenosine-to-inosine (A-to-I) RNA editing of microRNAs. A reduction of A-to-I editing in position 5 of miR-411-5p has been identified in several cancers, including NSCLC. In this study, thanks to cancer-associated gene expression analysis, we assessed the effect of the edited miR-411-5p on NSCLC cell lines. We found that edited miR-411-5p directly targets MET and negatively affects the itogen-activated protein kinases (MAPKs) pathway. Considering the predominant role of the MAPKs pathway on TKI resistance, we generated NSCLC EGFR mutated cell lines resistant to TKI inhibitors and evaluated the effect of edited miR-411-5p overexpression. We found that the edited miR-411-5p reduces proliferation and induces apoptosis, promoting EGFR TKI response in NSCLC-resistant cells\

ORGANISM(S): Homo sapiens

PROVIDER: GSE221334 | GEO | 2023/04/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A-to-I edited miR-411-5p targets MET and promotes TKI response in NSCLC-resistant cells

Project description:A-to-I edited miR-411-5p targets MET and promotes TKI response in NSCLC-resistant cells

| PRJNA913917 | ENA

Inhibition of ABCB1 Overcomes Cancer Stem Cell-like Properties and Acquired Resistance to MET inhibitor in Non-Small Cell Lung Cancer

Project description:Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations have shown a dramatic response to EGFR inhibitors (EGFR-TKI). EGFR T790M mutation and MET amplification have been recognized as major mechanisms of acquired resistance to EGFR-TKI. Therefore, MET inhibitors have recently been used in NSCLC patients in clinical trials. In this study, we tried to identify the mechanism of acquired resistance to MET inhibitor. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA-665752-resistant EBC1 cells, namely EBC1-R cells. EBC1-R cells showed overexpression of ATP-binding cassette sub-family B member 1 (ABCB1) as well as phosphorylation of MET. EBC1-R cells grew as cell spheres that exhibited cancer stem cell-like (CSC) properties and epithelial mesenchymal transition (EMT). The levels of two miRNAs, miR-374a and miR-138 which targeted ABCB1, were decreased in EBC1-R cells. ABCB1 siRNA and ABCB1 inhibitor elacridar could reduce sphere numbers and suppress EMT. Elacridar could also reverse the resistance to PHA-665752 in EBC1-R cells. Our study demonstrated that ABCB1 overexpression which was associated with CSC properties and EMT was involved in the acquired resistance to MET inhibitor. Inhibition of ABCB1 might be a novel therapeutic strategy for NSCLC patients with acquired resistance to MET inhibitor.

2015-03-07 | GSE66604 | GEO

PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target

Project description:Aberrant overexpression or activation of EGFR drives the development of non-small cell lung cancer (NSCLC) and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) by secondary EGFR mutations or c-MET amplification/activation remains as a major hurdle for NSCLC treatment. We previously identified WDR4 as a substrate adaptor of Cullin 4 ubiquitin ligase and an association of WDR4 high expression with poor prognosis of lung cancer. Here, using an unbiased ubiquitylome analysis, we uncover PTPN23, a component of the ESCRT complex, as a substrate of WDR4- based ubiquitin ligase. WDR4-mediated PTPN23 ubiquitination leads to its proteasomal degradation, thereby suppressing lysosome trafficking and degradation of wild type EGFR, EGFR mutant, and c-MET. Through this mechanism, WDR4 sustains EGFR and c-MET signaling to promote NSCLC proliferation, migration, invasion, stemness, and metastasis. Clinically, PTPN23 is downregulated in lung cancer and its low expression correlates with WDR4 high expression and poor prognosis. Targeting WDR4-mediated PTPN23 ubiquitination by a peptide that competes with PTPN23 for binding WDR4 promotes EGFR and c-MET degradation to block the growth and progression of EGFR TKI-resistant NSCLC. These findings identify a central role of WDR4/PTPN23 axis in EGFR and c-MET trafficking and a potential therapeutic target for treating EGFR TKI-resistant NSCLC.

2023-10-09 | PXD025361 | Pride

Acquired resistance mechanisms to capmatinib, a MET inhibitor in MET-amplified non-small cell lung cancer cells

Project description:Purpose: MET is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). To understand the mechanisms of resistance to MET-TKIs and establish therapeutic strategies, we developed an in vitro model using capmatinib-resistant cell lines (EBC-CR1, CR2, and CR3) derived from the MET-amplified NSCLC cell line EBC-1. Methods: We established capmatinib-resistant NSCLC cell lines from the MET-amplified NSCLC cell line EBC-1 and identified alternative signaling pathways using 3’mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative PCR and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the EBC-CR1, -CR2, and -CR3 resistant cell lines. Results: We found that epidermal growth factor (EGFR) mRNA expression and protein activation were increased in EBC-CR1–3 cells compared to EBC-1 cells. EBC-CR1 cells showed EGFR-dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells, which overexpressed the EGFR-MET heterodimer, responded dramatically to the combination of capmatinib and the phosphoinositide-3 kinase catalytic subunit α (PIK3CA) inhibitor afatinib. In addition, EBC-CR3 cells, which had activated EGFR along with amplified PIK3CA, were sensitive to the combination of afatinib and the PI3Kα inhibitor. Conclusions: Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be an effective therapeutic strategy in MET-TKI-resistant NSCLC patients.

2017-05-01 | GSE94405 | GEO

miR-205 mediates adaptive resistance to MET inhibition via ERRFI1 targeting and raised EGFR signaling

Project description:The onset of secondary resistance represents a major limitation to long term efficacy of target therapies in cancer patients. Thus, the identification of mechanisms mediating secondary resistance is key to the rational design of alternative therapeutic strategies for resistant patients. MiRNA profiling combined with RNA-seq in MET-addicted gastric and lung cancer cell lines led us to identify the miR-205/ERRFI1 (ERBB receptor feedback inhibitor-1) axis as a novel mediator of resistance to MET tyrosine kinase inhibitors (TKIs). In cells resistant to MET-TKIs, increased miR-205 expression determined the downregulation of the EGFR inhibitor ERRFI1, which, in turn, caused EGFR activation and MET-TKI resistance. MiR-205/ERRFI1 driven EGFR activation rendered MET-TKI resistant cells sensitive to combined MET/EGFR inhibition. As a proof of concept of the clinical relevance of this newly identified mechanism of adaptive resistance, we report that a patient with a MET amplified lung adenocarcinoma displayed deregulation of the miR-205/ERRFI1 axis in concomitance with the onset of clinical resistance to anti-MET therapy.

2018-07-16 | GSE114406 | GEO

An EGFR-mutation signature reveals features of the EGFR-dependent phenotype and identifies MACC1 as an EGFR-associated regulator of MET.

Project description:EGFR-mutated non-small cell lung cancers bear hallmarks including sensitivity to EGFR inhibitors, and low proliferation, and increased MET. However, the biology of EGFR dependence is still poorly understood. Using a training cohort of chemo-naive lung adenocarcinomas, we have developed a 72-gene signature that predicts (i) EGFR mutation status in four independent datasets; (ii) sensitivity to erlotinib in vitro; and (iii) improved survival, even in the wild-type EGFR subgroup. The signature includes differences associated with enhanced receptor tyrosine kinase (RTK) signaling, such as increased expression of endocytosis-related genes, decreased phosphatase levels, decreased expression of proliferation-related genes, increased folate receptor-1 (FOLR1) (a determinant of pemetrexed response), and higher levels of MACC1 (which we identify as a regulator of MET in EGFR-mutant NSCLC). Those observations provide evidence that the EGFR-mutant phenotype is associated with alterations in the cellular machinery that links the EGFR and MET pathways and create a permissive environment for RTK signaling. We have developed a gene expression signature that predicts (i) EGFR mutation in chemo-naive and, to a lesser extent, in chemo-refractory NSCLC patients; (ii) EGFR TKI response in vitro; and (iii) survival in wild-type EGFR patients. The signature also identifies novel features of EGFR mutant NSCLC including increased levels of endocytosis-related genes and MACC1, which appears be an EGFR mutant associated regulator of MET. Gene expression profiles were measured in 124 core biopsies from patients with refractory non-small cell lung cancer in the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial. We used the BATTLE dataset to test an EGFR-mutation gene expression signature trained in chemo-naive lung adenocarcinoma. The signature was computed as an index, called EGFR index.

2014-06-01 | E-GEOD-31852 | biostudies-arrayexpress

An EGFR-mutation signature reveals features of the EGFR-dependent phenotype and identifies MACC1 as an EGFR-associated regulator of MET.

2014-06-01 | GSE31852 | GEO

Whole exome sequencing of EGFR-TKI naive and EGFR-TKI resistant lung adenocarcinoma samples

Project description:Whole exome sequencing was performed on set of 48 DNA samples obtained from 16 EGFR mutated NSCLC patients whose tumors progressed following EGFR-TKI treatment. The DNA samples included baseline biopsy, rebiopsy and blood from the same patient. By comparing the variants in rebiopsy tumors and baseline tumors we aim to understand the genomic alterations responsible for the development of EGFR-TKI resistance in NSCLC patients.

2022-02-11 | E-MTAB-11404 | biostudies-arrayexpress

TKI-resistant T790M EGFR Mutation Rewired EGFR Translocation Routes through Switching Interactome in Non-Small Cell Lung Cancer

Project description:Epidermal growth factor receptor (EGFR) harboring active mutations, Del19 and L858R, are most common oncogenic mutations in in non-small cell lung cancer (NSCLC) patients. The preferred treatment at first line is tyrosine kinase inhibitor (TKI) administration while the TKI-resistance usually develops because of acquiring the secondary EGFR T790M mutant. Protein-protein interactions (PPIs) constitute the signaling scaffold and thus aberrant PPIs ascribed to mutations often results in dysregulations of downstream signaling cascades. Affinity purification coupled mass spectrometry (AP-MS) was utilized to characterize the EGFR PPIs in four NSCLC cells which carry different EGFR subtypes representing as TKI-sensitive and -resistant models in this study. The EGFR interactomes of TKI-resistant NSCLC cells presented higher diversity of subcellular distribution as well as the hyperactive EGFR trafficking. Furthermore, gefitinib perturbation activated autophagy-mediated EGFR degradation in TKI-resistant NSCLC models and inhibiting autophagy process indeed reduced the TKI-resistance against gefitinib as cytotoxicity was significantly improved. Alternatively, gefitinib induced EGFR translocation toward cell periphery through Rab7 ubiquitination in TKI-sensitive models which may confer TKIs more chance to suppress EGFR activity. In brief, acquired T790M EGFR mutation rewired the EGFR inherent interactomes and thus guided EGFR moving toward distinct trafficking routes, EGFR recycling or autophagy-mediated degradation, in response to TKI insult in TKI-sensitive and -resistant NSCLC cells. These finding suggest that manipulation or combined autophagy inhibition may provide us a novel therapeutic strategy to manage TKI-resistance and tumor relapse in NSCLC.

2023-05-31 | PXD034228 | JPOST Repository

Microarray study to understand acquired resistance to EGFR-targeted therapy in lung cancer

Project description:Activating mutations of EGFR have been characterized as important mechanisms for carcinogenesis in a subset of EGFR-dependent non-small cell lung cancers (NSCLC). EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, have dramatic clinical effects on EGFR-addicted lung cancers and are used as first-line therapy for EGFR-mutant tumors. However, eventually all tumors acquire secondary resistance to the drugs and progress. We established a model to better understand mechanisms of acquired resistance. NCI- HCC827 cells are EGFR-mutant and highly erlotinib-sensitive. In this study we exposed HCC827 cells to increasing concentrations of erlotinib and two highly erlotinib-resistant subclones were developed (ER3 and T15-2). In these subclones no acquired alterations of EGFR or MET were found. We hereby performed a gene expression microarray studies to understand changes that might explain mechanisms of resistance. Through these studies we demonstrated in one resistant clone (ER3) overexpression of AXL, a tyrosine kinase implicated in imatinib and lapatinib resistance. Gene expression profilings were measured in NSCLC cell line HCC827 and two erlotinib-resistant HCC827-originated sublines ER3 and T15-2.

2012-05-29 | E-GEOD-38310 | biostudies-arrayexpress

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