Gene expression data in the human non-small cell lung cancer cell line NCI-H1975 and osimertinib-resistant OR1 and OR2 cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE201608 | GEO | 2022/04/28
REPOSITORIES: GEO
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Project description:Osimertinib resistant cells of H1975
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Project description:Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is a highly effective and valuable treatment option for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, like T790M. However, acquired resistance ultimately limits its clinical application. In this study, we constructed H1975/OSI cell lines and utilized potentially complementary transcriptomic and proteomic techniques, which may provide insight into the intricately complex molecular mechanisms, to reveal potential therapeutic targets associated with Osimertinib resistance. Uni-omics and multi-omics analyses were conducted on the transcriptomic and proteomic (4D label-free) expression profiles, which involved differential expression analysis, GO functional annotation and KEGG pathway enrichment analysis, correlation analysis of transcription factors, PPI network and Cytoscape analysis. We highlighted multiple signaling pathways and eleven hub-genes, including NOP56, DDX21, PDCD11, CCNB1, TOP21, KPNA2, DDX5, EFTUD2, BRCA1, LMNB1 and HIF1A, that may be the key to overcoming resistance. Further validation of these targets and molecules in preclinical and clinical studies could lead to the development of new and more effective treatment options for H1975-resistant patients.
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Project description:Oncogenic signals often activate abnormal proliferation, while simultaneously activate stress-adaptive mechanisms such as the integrated stress response (ISR) to ensure rapid growth under intrinsic and extrinsic stress conditions. In this study, we investigated the involvement of EGFR-PI3K pathway in the regulation of ISR in EGFR-mutant NSCLC cell lines under amino acid deprivation. We found that the third generation EGFR inhibitor osiemrtinib suppressed induction of activation transcription factor 4 (ATF4), the key ISR effector, in EGFR mutant cells, while the effect was to a less extent in cells harboring PIK3CA-co-alteration. PI3K inhibitors including P110a-specific inhibitor alpelicib markedly suppress ATF4 induction in PIK3CA-mutant cell lines. To further explore the role of EGFR-PI3K, transcriptome analysis was performed in EGFR- and PIK3CA-mutated NCI-H1975 cells treated with osimertinib, alpelisib, or combination of these in the absence or presence of histidyl-tRNA inhibitor L-histidinol (His), mimicking amino acid deprived conditions. Among His-induced genes, either osimertinib or alpelisib partially, but the combination dramatically suppressed a cluster of genes targeted by ATF4. Furthermore, combination of osimertinib and alpelisib increased apoptotic cells under amino acid deprived conditions. These results indicate that oncogenic EGFR-PI3K pathway contributes to cellular adaptation to stress conditions through ATF4. We used microarrays to identify genes whose expression is up- or down-regulated by inhibition of EGFR, PI3K, or both under amino acid deprivation.
2023-03-22 | GSE216508 | GEO
Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Our study identifies ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. To generate drug-resistant NCI-H1975 cell lines, non-small cell lung cancer (NSCLC) cells were exposed to increasing concentrations of WZ4002 similar to previously described methods. Individual clones from WZ4002-resistant (WZR) cells were isolated and confirmed to be drug resistant. Clone #6, designated as WZR6, was used in this study. For expression analysis, samples were prepared in triplicate from parental NCI-H1975 and NCI-H1975 WZR6 cells.
2012-10-01 | E-GEOD-37699 | biostudies-arrayexpress
Project description:Further to our previous study (E-MTAB-5997), here we performed transcriptome profiling on Anlotinib-resistant NCI-H1975 and Anlotinib-treated Anlotinib-resistant NCI-H1975, and would like to understand the effects of Anlotinib on Anlotinib-resistant NCI-H1975 cell, compare the different transcriptome profiling on NCI-H1975 cells and Anlotinib-resistant NCI-H1975 cells, sought to find the biomarker for explaining Anlotinib resistance.
2019-07-01 | E-MTAB-7068 | biostudies-arrayexpress
Project description:Even after osimertinib is administered to lung adenocarcinomas with EGFR mutations, there are a few cells which survive, and these tolerant cells are considered to be the source of later recurrence. We used microarray analysis to explore the mechanism behind the tolerance to osimertinib in lung adenocarcinoma cells with EGFR mutations.
2022-04-16 | GSE200893 | GEO
Project description:Lung cancer continues to be the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are two 3rd generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance to it. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rd generation EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative proteomic and phosphoproteomic dataset to uncover alterations in signaling pathways, and to reveal a proteomic signature of EMT and kinases / phosphatases with altered protein expression and phosphorylation in the TKI resistant cells. We validated the significant role of SHP2 in the activation of RAS/MAPK and PI3K/AKT signaling pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified that dactolisib, a PI3K/mTOR inhibitor, in combination with osimertinib, may overcome osimertinib resistance both in vitro and in vivo. Introduction Lung cancer continues to be the leading cause of cancer mortality in the world (1). Many lung adenocarcinoma patients with activating epidermal growth factor receptor (EGFR) mutations initially respond dramaticlly to the first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). However, they eventually develop resistance. The most common mechanism of acquired resistance is the EGFR T790M gatekeeper site residue mutation (2). Osimertinib, a third generation irreversible EGFR TKI has been approved by the FDA to treat patients harboring the EGFR T790M mutation who have developed resistance to first- and second- generation EGFR TKIs (3). Recently, osimertinib was also approved for the front-line treatment of patients harboring EGFR mutations (4). Rociletinib is another irreversible inhibitor targeting the EGFR T790M mutation, which has minimal activity against wild-type EGFR. Both drugs have therapeutic benefits and have demonstrated activity in tumors with T790M-mediated resistance to other EGFR tyrosine kinase inhibitors (5, 6). Further development of rociletinib was ceased in 2016 due to less than expected efficacy, poor brain penetration leading to tumor progression in brain tissues and off-target effects on IGFR activation leading to hyperglycemia (7, 8). Although 3rd-generation TKIs provide clinical benefit to most patients with EGFR mutations, some patients, demonstrating primary resistance, still do not respond to these inhibitors. Complete responses are rare, and all patients eventually develop resistance, suggesting primary and acquired resistance mechanisms decrease the efficacy of the drugs (9, 10). Genomic approaches have been used primarily to interrogate osimertinib resistance mechanisms (9, 11-15). Several mechanisms of osimertinib resistance have been identified (16), including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events (17). However, the resistance mechanism is complex and still not fully understood. Previously, we have used SILAC-based quantitative phosphoproteomics to identify the global dynamic modification which occur upon treatment of TKI-sensitive and -resistant lung adenocarcinoma cells with the 1st and 2nd generation EGFR TKIs, erlotinib and afatinib. Utilizing this strategy, we identified the targets of mutant EGFR signaling pathways responsible for TKI resistance, and possible off-target effects of the drugs (18, 19). In this study, we employed SILAC-based quantitative mass spectrometry to characterize alterations in the proteome and phosphoproteome which occur upon acquired resistance and sought to identify novel mechanisms of resistance to the third generation EGFR TKIs, osimertinib and rociletinib. To our knowledge, this is the most comprehensive 3rd generation EGFR TKI resistant proteome and phosphoproteome analysis resource available to date.
2021-03-11 | PXD020108 | Pride
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.
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Project description:The H1975 osimertinib resistant (H1975 OR) cell lines were successfully established by subjecting parental H1975 cells to a gradually increasing concentration of osimertinib up to 1μM for a duration exceeding 2 months. In order to investigate the molecular alterations associated with osimertinib resistance, we analyzed the transcriptional profiling of parental H1975 cells and H1975 OR cells by RNA sequencing.
2024-08-01 | GSE272162 | GEO
Project description:Genome variation profiling of lung adenocarcinoma cells comparing untreated NCI-H1975 cells with CNX-2006-resistant untreated cells. Goal was to determine the potential mechanism of resistance to mutant EGFR-TKIs and rationally design novel strategies for the treatment of EGFR-mutant lung cancer patients. Two-condition experiment: NCI-H1975 parental cells vs CNX-2006-resistant cells. Pooled DNA from healthy volunteers was used as reference.
2015-07-01 | E-GEOD-53234 | biostudies-arrayexpress