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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

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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

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

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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

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