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Analysis of the lncRNA-miRNA-mRNA network reveals a potential regulatory mechanism of EGFR-TKIs resistance in NSCLC

ABSTRACT: In this study, to investigate the underlying molecular mechanisms of how EGFR-TKIs resistance occurs in NSCLC, we examined gene expression using microarray technology on gefitinib-resistant NSCLC cells to obtain differentially expressed (DE) lncRNAs and mRNAs. Then we carried out KEGG enrichment analysis for DE-mRNAs and constructed the ceRNA regulatory network of DE-lncRNAs and DE-mRNAs. Our results revealed the downregulated lncRNA LINC01128 acted as ceRNA to decrease PTEN via sponging miR-25-3p, and then the signal reactions caused by the reduction of PTEN would activate PI3K/Akt signaling pathway, which may lead to the development of drug resistance to EGFR-TKIs in NSCLC. Our findings will provide a novel perspective for the underlying molecular mechanisms of EGFR-TKIs resistance in NSCLC. Besides, this research will help to develop new therapeutic targets for EGFR-TKIs resistance in NSCLC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193628 | GEO | 2022/01/14

REPOSITORIES: GEO

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Project description:Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Examination of mRNA levels in DMSO and gefitinib-resistant cultures of HCC4006 and HCC827. Each group has two replicates.

Project description:Bidkhori2012 - EGFR signalling in NSCLC The paper describes and compares two models on EGFR signalling between normal and NSCLC cells. Moreover, it is shown that ERK (MAPK), STAT and Akt factor's activation pattern are different between normal and NSCLA models. This model corresponds to EGFR signalling in NSCLA cells. Created by The MathWorks, Inc. SimBiology tool, Version 3.3 This model is described in the article: Modeling of tumor progression in NSCLC and intrinsic resistance to TKI in loss of PTEN expression. Bidkhori G, Moeini A, Masoudi-Nejad A PloS one [2012, 7(10):e48004] Abstract: EGFR signaling plays a very important role in NSCLC. It activates Ras/ERK, PI3K/Akt and STAT activation pathways. These are the main pathways for cell proliferation and survival. We have developed two mathematical models to relate to the different EGFR signaling in NSCLC and normal cells in the presence or absence of EGFR and PTEN mutations. The dynamics of downstream signaling pathways vary in the disease state and activation of some factors can be indicative of drug resistance. Our simulation denotes the effect of EGFR mutations and increased expression of certain factors in NSCLC EGFR signaling on each of the three pathways where levels of pERK, pSTAT and pAkt are increased. Over activation of ERK, Akt and STAT3 which are the main cell proliferation and survival factors act as promoting factors for tumor progression in NSCLC. In case of loss of PTEN, Akt activity level is considerably increased. Our simulation results show that in the presence of erlotinib, downstream factors i.e. pAkt, pSTAT3 and pERK are inhibited. However, in case of loss of PTEN expression in the presence of erlotinib, pAkt level would not decrease which demonstrates that these cells are resistant to erlotinib. This model is hosted on BioModels Database and identified by: MODEL1304020001 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Analysis of the lncRNA-miRNA-mRNA network reveals a potential regulatory mechanism of EGFR-TKIs resistance in NSCLC

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