Transcriptomic analysis of epithelial to mesenchymal transition in EGFR-mutant NSCLC cell lines.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE123031 | GEO | 2019/12/31
REPOSITORIES: GEO
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Project description:We have employed a transcriptomic approach to find a molecular target that could compensate for the loss of EGFR signaling in NSCLC cell lines with acquired resistance to gefitinib with an EMT phenotype.
2019-12-31 | GSE123066 | GEO
Project description:Acquired drug resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), therapeutic failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with resistance to EGFR TKIs in both experimental models and in patients, and may coincide with genetic mechanisms of resistance such as the EGFRT790M gatekeeper mutation. While therapeutic approaches targeting EGFRT790M have been developed, a strategy for overcoming EMT-related resistance remains unclear. We performed whole-genome CRISPR screening on patient-derived, mesenchymal EGFRT790M-positive cell lines and identified FGFR1 as a critical gene promoting resistance to third generation EGFR TKIs. The FGFR1-3 inhibitor, BGJ398 (infigratinib), resensitized resistant mesenchymal-like cell lines to EGFR inhibition in a synergistic manner. Combining EGFR + FGFR inhibitors also inhibited the in vitro survival and expansion of EGFR mutant drug tolerant cells with mesenchymal-like features prior to the development of drug resistance, and delayed the development of in vivo resistance in EGFR mutant NSCLC xenograft tumors. These results suggest that dual EGFR + FGFR blockade may be a promising clinical strategy for preventing and overcoming EMT-associated acquired drug resistance in EGFR mutant NSCLC.
2019-04-30 | GSE114647 | GEO
Project description:Introduction: Overcoming of acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable obstacle for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are very complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR mutated lung cancer largely unknown. Methods: Osimertinib and afatinib-resistant EGFR-mutated lung cancer cells were established using by a stepwise method. Microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant NSCLC cells. Results: Microarray analysis was evaluated by bioinformatics analysis through medical-industrial collaboration. CRNDE and DGCR5 lncRNAs were highly expressed in EGFR-TKIs-resistant cells. CRNDE binds to eIF4A3 protein, down-regulates eIF4A3 and MUC1 expression, and down-regulates p-EGFR expression. CRNDE inhibition activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity and restored sensitivity to EGFR-TKIs. Conclusions: We identified lncRNA CRNDE associated with resistance to EGFR-TKIs in EGFR-mutant NSCLC cells. CRNDE may be a novel therapeutic target for EGFR mutant NSCLC patients.
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Project description:Non-small cell lung cancers (NSCLCs) harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as erlotinib and geffitinib. However, nearly all patients show relapse within 1 year after initial treatment. We used microarrays to detail global gene expression changes in EGFR mutant cells vs. WT cells responding to erlotinib. 4 EGFR mutant and 4 WT NSCLC cells were treated with or without erlotinib for 24 hr, followed by RNA extraction and hybridization on Affymetrix microarrays.
2014-05-16 | E-GEOD-57156 | biostudies-arrayexpress
Project description: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.
2022-01-14 | GSE193628 | GEO
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.
2016-03-29 | E-GEOD-79688 | biostudies-arrayexpress
Project description:The Epidermal Growth Factor Receptor (EGFR) regulates a diverse set of biological processes including cell growth, proliferation, and differentiation. Deregulation of the EGFR pathway has been implicated in a variety of human diseases including cancer. Gefitinib and erlotinib are tyrosine kinase inhibitors (TKIs) that have demonstrated clinical benefit for patients with Non-small cell lung cancer (NSCLC) and EGFR activating mutations. However, patients invariably acquire resistance to TKI treatment through a number of mechanisms. We utilized in vitro models of NSCLC with EGFR activating mutations and derived three isogenic cell lines with acquired resistance to gefitinib. We next studied genomewide mRNA expression in resistance and wild type cells and their effect in the reprogramming of pathways in lung cancer cell line models..
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Project description:The Epidermal Growth Factor Receptor (EGFR) regulates a diverse set of biological processes including cell growth, proliferation, and differentiation. Deregulation of the EGFR pathway has been implicated in a variety of human diseases including cancer. Gefitinib and erlotinib are tyrosine kinase inhibitors (TKIs) that have demonstrated clinical benefit for patients with Non-small cell lung cancer (NSCLC) and EGFR activating mutations. However, patients invariably acquire resistance to TKI treatment through a number of mechanisms. We utilized in vitro models of NSCLC with EGFR activating mutations and derived three isogenic cell lines with acquired resistance to gefitinib. We next studied genomewide mRNA expression in resistance and wild type cells and their effect in the reprogramming of pathways in lung cancer cell line models..
2017-06-02 | GSE95558 | GEO
Project description:Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been recommended as the first line therapy for non-small cell lung cancer (NSCLC) with EGFR mutations. However, acquired resistance to EGFR-TKIs is inevitable. Although anti- programmed cell death 1 (PD-1)/PD-ligand (PD-L1) immunotherapies have achieved great clinical success as second-line treatment for many cancer types, the clinical efficacy of anti-PD-1/PD-L1 blockades in EGFR mutated NSCLC patients has been demonstrated to be obviously lower than those without EGFR mutations. Here, we reported an advanced NSCLC patient with exon 19 deletion and T790M EGFR mutation benefitting from anti-PD-1 blockade therapy after acquiring resistance to EGFR-TKI. We characterized the mutational landscape of the patient with next-generation sequencing (NGS), and successfully identified neoantigen-specific T cell clones derived from EGFR exon 19 deletion, TP53 A116T and DENND6B R398Q mutations. Our findings support the potential application of immune checkpoint blockades in NSCLC patients with acquired resistance to EGFR-TKIs in the context of specific clonal neoantigens with high immunogenicity. Personalized immunomodulatory therapy targeting these neoantigens should be explored for better clinical outcomes in EGFR mutant NSCLC patients.
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Project description:Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non–small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs in lung cancer cells remains an inevitable problem: ALK secondary mutations and bypass pathways have been reported as major resistance mechanisms. In this study, we aimed to discover a novel mechanism of acquired resistance to ALK-TKIs and a strategy to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)–resistant H2228 non-small cell lung cancer cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial–mesenchymal transition (EMT), and had cancer stem cell–like properties. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI–resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI–resistance and EMT changes in both ALK-TKI–resistant and TGF-β1–exposed H2228 cells. Progression-free survival of ALK-positive NSCLC patients with AXL overexpression was shorter than that of patients who underwent crizotinib therapy and showed low AXL expression. Thus, we found ALK signaling-independent AXL overexpression and EMT features were commonly involved in intrinsic and acquired resistance to first and second generation ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome tumor cells in ALK-positive NSCLC patients.
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