Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1209961 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31983408_1.fastq.gz | Fastqsanger.gz | |||
| SRR31983408_2.fastq.gz | Fastqsanger.gz | |||
| SRR31983409_1.fastq.gz | Fastqsanger.gz | |||
| SRR31983409_2.fastq.gz | Fastqsanger.gz | |||
| SRR31983410_1.fastq.gz | Fastqsanger.gz |
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Project description:Lung adenocarcinoma (LUAD) is the most common type of lung cancer. Resistance to osimertinib, a 3rd generation EGFR-TKI, develops within 12 months in patients with EGFR T790M mutation. This study used RNA-seq to identify circular RNAs (circRNAs) regulating osimertinib resistance in LUAD. We identified circSPINT2 as downregulated in osimertinib-resistant cell lines (OR3, OR4, OR6, HOsR) compared to parental H1975 cells. circSPINT2 enhances osimertinib sensitivity by inducing apoptosis via the hsa-miR-1296-3p/RBP1 axis. circSPINT2 is proposed as a non-invasive biomarker for monitoring osimertinib resistance in LUAD.
2025-11-14 | GSE295915 | GEO
Project description:Aberrant epigenetic regulation is closely associated with drug tolerance, an early step in the acquisition of drug resistance. We previously reported that a pioneer transcriptional factor (also called an epigenetic initiator) rapidly induced by osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, plays a pivotal role in promoting the formation of osimertinib-tolerant cells. In this study, to identify novel epigenetic factors associated with osimertinib-tolerance, we performed a comprehensive screening of epigenetic factors whose expression is rapidly induced by osimertinib. Our results revealed that HDAC5, a class IIa histone deacetylase (HDAC), is the most prominently induced epigenetic factor in EGFR-mutant non-small cell lung cancer (NSCLC) cell lines during the early response to osimertinib. Knockdown of HDAC5 significantly reduced the emergence of osimertinib-resistant cells. Furthermore, treatment with LMK235, a selective HDAC5 inhibitor, significantly increased global histone acetylation and enhanced osimertinib-induced apoptosis. These findings underscore the potential of HDAC5 as a novel therapeutic target to overcome osimertinib-resistance and propose LMK235 as a promising compound to provide significant therapeutic benefits for EGFR-mutant NSCLC patients undergoing osimertinib treatment.
2025-04-30 | GSE283536 | 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:Background: The emergence of acquired resistance to osimertinib represents a formidable therapeutic challenge in the management of non-small cell lung cancer (NSCLC). While circular RNAs (circRNAs) have been increasingly recognized as crucial modulators of chemotherapeutic resistance, their specific involvement in osimertinib resistance mechanisms remains poorly elucidated. Methods: We established osimertinib-resistant NSCLC cell lines (HCC4006OR) through prolonged drug exposure and conducted comprehensive transcriptome sequencing to identify differentially expressed circRNAs. The molecular characteristics and functional implications of circROBO2 were systematically investigated utilizing an array of cellular and molecular biological methodologies. Advanced molecular dynamics simulations were implemented to elucidate the potential molecular interactions between PDGFB and osimertinib. Results: We identified circROBO2 as significantly upregulated in osimertinib-resistant HCC4006OR cells. Functional studies revealed that circROBO2 enhances cell survival, proliferation, and invasion while suppressing apoptosis under osimertinib treatment. Mechanistically, circROBO2 functions as a molecular sponge for miR-625-5p, resulting in elevated PDGFB expression and subsequent activation of the MAPK pathway, particularly the RAF/MEK/ERK cascade. Targeting this pathway through circROBO2 knockdown or miR-625-5p overexpression partially restored osimertinib sensitivity in resistant cells. Molecular dynamics simulations suggested potential direct interactions between PDGFB and osimertinib, providing additional insights into the resistance mechanism. Conclusions: Our study identifies a novel circROBO2/miR-625-5p/PDGFB regulatory axis in osimertinib resistance and positions circROBO2 as a potential therapeutic target and biomarker for NSCLC treatment.
2026-06-30 | GSE301232 | GEO
Project description:In this study, we evaluate the therapeutic potential of combining osimertinib with pemetrexed and clarify the underlying molecular mechanisms in order to establish novel therapeutic strategies for EGFR-mutant NSCLC. We found that the combination of osimertinib and pemetrexed could induce strong apoptotic activity and enhance anti-tumor effects compared to monotherapy in two NSCLC cell lines harboring an EGFR mutation. In addition, we have identified PLK1 as a therapeutic target for combination therapy and as a promising treatment target for overcoming resistance to osimertinib in EGFR-mutated NSCLC patients.
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Project description:Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. Whilst patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq, ChIP-seq, and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic opportunities.
2022-04-06 | GSE193257 | GEO
Project description:Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. Whilst patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq, ChIP-seq, and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic opportunities.
2022-04-06 | GSE193256 | GEO
Project description:Untargeted lipidomics on pharmacologically-induced non-small cell lung cancer cell models of osimertinib resistance (PC9R5 and PC9R6) and osimertinib sensitive control (PC9P). Six replicates per condition.
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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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