Ontology highlight
ABSTRACT:
PROVIDER: PRJNA649080 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12335539.fastq.gz | Fastqsanger.gz | |||
| SRR12335540.fastq.gz | Fastqsanger.gz |
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Project description:The model is based on publication:
Mathematical analysis of gefitinib resistance of lung adenocarcinoma caused by MET amplification
Abstract:
Gefitinib, one of the tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR), is effective for treating lung adenocarcinoma harboring EGFR mutation; but later, most cases acquire a resistance to gefitinib. One of the mechanisms conferring gefitinib resistance to lung adenocarcinoma is the amplification of the MET gene, which is observed in 5–22% of gefitinib-resistant tumors. A previous study suggested that MET amplification could cause gefitinib resistance by driving ErbB3-dependent activation of the PI3K pathway. In this study, we built a mathematical model of gefitinib resistance caused by MET amplification using lung adenocarcinoma HCC827-GR (gefitinib resistant) cells. The molecular reactions involved in gefitinib resistance consisted of dimerization and phosphorylation of three molecules, EGFR, ErbB3, and MET were described by a series of ordinary differential equations. To perform a computer simulation, we quantified each molecule on the cell surface using flow cytometry and estimated unknown parameters by dimensional analysis. Our simulation showed that the number of active ErbB3 molecules is around a hundred-fold smaller than that of active MET molecules. Limited contribution of ErbB3 in gefitinib resistance by MET amplification is also demonstrated using HCC827-GR cells in culture experiments. Our mathematical model provides a quantitative understanding of the molecular reactions underlying drug resistance.
2024-09-02 | BIOMD0000000827 | BioModels
Project description:Epithelial-mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non-small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA) -related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) in NSCLC. MiRNA expression profiles were examined before and after transforming growth factor-beta1 (TGF-M-NM-21) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. MiRNA array and quantitative RT-PCR revealed that TGF-M-NM-21 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN (phosphatase and tensin homolog), was diminished in A549 cells with EMT after the TGF-M-NM-21 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-M-NM-21-induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-M-NM-21-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, whose suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be new therapeutic targets in advanced lung adenocarcinoma patients, depending on the EMT phenomenon. miRNA expression profiles before and after TGF-M-NM-21 exposure were assessed in the four lung adenocarcinoma cell lines, A549, LC2/ad, PC3, and, PC9 by TaqMan miRNA arrays. Relative ratios of miRNAs in cells after TGF-M-NM-21 exposure were calculated when compared with the cells before TGF-M-NM-21 exposure.
2013-10-30 | E-GEOD-51828 | biostudies-arrayexpress
Project description:In this study, we established an gefitinib resistant lung adenocarcinoma cell line (i.e. PC9/GR) from lung adenocarcinoma PC9 cell line which was sensitive to gefitinib. Then microarray was performed to elucidate the lncRNAs, cirRNAs and mRNAs involved in gefitinib resistance.
2022-04-11 | GSE169513 | GEO
Project description:Epithelial-mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non-small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA) -related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine-kinase inhibitor (EGFR-TKI) in NSCLC. MiRNA expression profiles were examined before and after transforming growth factor-beta1 (TGF-β1) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. MiRNA array and quantitative RT-PCR revealed that TGF-β1 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN (phosphatase and tensin homolog), was diminished in A549 cells with EMT after the TGF-β1 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-β1-induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-β1-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, whose suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be new therapeutic targets in advanced lung adenocarcinoma patients, depending on the EMT phenomenon.
2013-10-30 | GSE51828 | GEO
Project description:Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Prolonged cancer treatment will induce the development of acquired resistance to EGFR TKI. To gain insight into the molecular mechanisms of EGFR-TKIs resistance, we generate EGFR-TKI-resistant HCC827-8-1 cells to be analyzed by microarray with their parental HCC827cells. gefitinib resistant HCC827-8-1 cells with three replications; gefitinib-sensitive HCC827 cells with three replications
2016-08-23 | E-GEOD-74575 | biostudies-arrayexpress
Project description:gefitinib-resistant lung adenocarcinoma cell lines（PC9/GR）transfect HUMT-specific shHUMT to knockdown HUMT1 and analysis differential gefitinib-resistant lung adenocarcinoma cell lines（PC9/GR）transfect HUMT-specific shHUMT to knockdown HUMT1 and analysis differential
2021-07-06 | GSE179146 | GEO
Project description:Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), induces substantial clinical responses for non-small cell lung cancer (NSCLC) cells harboring EGFR activating mutations, but most of them invariably develop resistance. By generating a gefitinib resistance (PC9GR) from a human NSCLC-derived drug sensitive cell line (PC9), we studied differences of transcription dynamics between them by the aid of a computational decoupling of hidden regulatory signals from time course gene expression profiles. Given a collection of transcription factors (TFs) and their regulatory targets, the method captured temporally-synchronized shifts in evolving expression of target genes sharing each TF regulatory unit, and drew underlying regulatory signals. The analysis identified sterol regulatory element binding protein 1 (SREBP-1) as a key regulatory agent that facilitates the maintenance of drug tolerance, involving transcription controls of a G1-specific cyclin dependent kinase inhibitor whose expression was specifically elevated in PC9, but in turn, reduced in PC9GR Gefitinib-resistance cell line (PC9GR) was established derived from lung adenocarcinoma cell line PC9. PC9 cells and PC9GR cells were treated with the four different conditions, control (No treatment), EGF-treatment, gefitinib-treatment, and both gefitinib and EGF-treatment. In each condition, the gene expression was measured at 26 time points during 24 hrs.
2014-01-01 | E-GEOD-34228 | biostudies-arrayexpress
Project description:Purpose: To characterize microRNA signatures for tolerance, persistence and resistance to EGFR tyrosine kinase inhibitors (TKIs) in human lung cancer. Methods: microRNA profiles of gefitinib- and osimertinib-tolerant cells in PC9 and HCC827 cells were generated by deep microRNA sequencing using Illumina. In addition, microRNA profiles of PC9 subpopulations cells with characterizations of persistence and resistance to gefitinib were generated by deep microRNA sequencing. The mappable reads were aligned to the human genome and miRbase using Bowtie. Results: We identified a specific microRNA profile distinguishing tolerance, persistence and resistance to gefitinib or osimertinib from parental human lung cancer cells with mutated EGFR. The expressions of those microRNAs in lung cancer cells were validated by qRT-PCR. Functionally, knocking down top-upregulated microRNAs reduced the tolerance, persistence and resistance to gefitinib or osimertinib in those tolerant and resistant cells. Conversely, overexpression of those microRNAs enhanced the tolerance and resistance to EGFR inhibition in cells sensitive to gefitinib and osimertinib. Conclusions: Our work identifies a panel of microRNAs that mediate EGFR-TKI tolerance and resistance in lung cancer. Our study provides potential non-coding targets to improve the efficacy of EGFR-TKIs therapy in cancer pagtients.
2018-01-11 | GSE103352 | GEO
Project description:To identify novel miRNAs involved in acquired EGFR TKI resistance in NSCLC, genome-wide miRNA expression analysis was performed in gefitinib-resistant sub-cell lines and gefitinib-sensitive parental cell lines.
2018-02-21 | GSE110815 | GEO