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Genome-wide analysis of gefitinib short-term resistance gene expression in the NSCLC cell line PC9 in co-culture

ABSTRACT: Analysis of gefitinib short-term resistance at gene expression level. The hyposthesis tested in the present study was that short-term resistance towards gefitinib in NSCLC cells influences pathways that associates with resistance towards EGFR-TKI treatment. Results provide important information of the response of EGFR mutant NSCLC cells to gefitinib and also to resistance towards gefitinib resistance, up-or down-regulated specific resistance pathways and cellular functions. Total RNA obtained from PC9 cell line (n=3), co-cultured PC9 (with MRC-5 cells)(n=3), gefitinib treated (0.5ÂµM) PC9 (n=3), and co-cultured (MRC-5) + gefitinib treated PC9 cells (n=3) for 48h after gefitinib treatment

ORGANISM(S): Homo sapiens

SUBMITTER: Sajo Kaduthanam

PROVIDER: E-GEOD-75308 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Genome-wide analysis of gefitinib short-term resistance gene expression in the NSCLC cell line HCC827 in co-culture

Project description:Analysis of gefitinib short-term resistance at gene expression level. The hyposthesis tested in the present study was that short-term resistance towards gefitinib in NSCLC cells influences pathways that associates with resistance towards EGFR-TKI treatment. Results provide important information of the response of EGFR mutant NSCLC cells to gefitinib and also to resistance towards gefitinib resistance, up-or down-regulated specific resistance pathways and cellular functions. Total RNA obtained from HCC827 cell line (n=3), co-cultured HCC827 (with MRC-5 cells)(n=3), gefitinib treated (0.5ÂµM) HCC827 (n=3), and co-cultured (MRC-5) + gefitinib treated HCC827 cells (n=3) for 48h after gefitinib treatment

2016-07-01 | E-GEOD-75307 | biostudies-arrayexpress

Genome-wide analysis of gefitinib short-term resistance gene expression in the NSCLC cell line PC9 in co-culture

2016-07-01 | GSE75308 | GEO

Genome-wide analysis of gefitinib short-term resistance gene expression in the NSCLC cell line HCC827 in co-culture

2016-07-01 | GSE75307 | GEO

Time-course gene expression profiles of gefitinib-sensitive or -resistant lung adenocarcinoma cells stimulated with EGF, in the presence or absence of gefitinib, EGF receptor tyrosine kinase-specific inhibitor

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

Transcriptome analysis of PC9 cells with gefitinib or/and hypoxia treatment and comparison with gefitinib resistant PC9 cells and ALDH positive PC9 cells

Project description:Inevitable gefitinib resistance and relapse of the disease was the biggest hurdle to NSCLC treatment. Importantly, the role of hypoxia in solid tumor tissues in vivo in gefitinib acquired resistance and its relationship to lung cancer stem cells (LCSCs) has not been fully elucidated. Here, the PC9 cells were treated with short term gefitinib or/and hypoxia, also, PC9 gefitnib resistant (PC9-GR) cell line was established and ALDH positive PC9 cells were sorted by FACs. Transcriptome analysis among those PC9 cell groups revealed the important role of hypoxia in gefitinib acquired resistance and signaling transduction change, which may critical for NSCLC disease progression and recurrence.

2017-10-31 | GSE69599 | GEO

Resistance to Irreversible EGFR Tyrosine Kinase Inhibitors through a Multistep Mechanism Involving the IGF1R Pathway

Project description:The clinical efficacy of EGFR kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or by the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study we develop drug resistant versions of the EGFR mutant PC9 cell line which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804 resistant (PFR) or WZ4002 resistant (WZR) clones of PC9 harbor EGFR T790M. Instead, they demonstrate activated IGF1R signaling as a result of loss of expression of IGFBP3 and the IGF1R inhibitor, BMS 536924, restores EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug resistant subclone which contains ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR mutant NSCLC. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways activated in resistant cancers before they emerge, may be a more effective clinical strategy. Total of three samples with duplicate or triplicate each were analyzed.

2012-10-01 | E-GEOD-38404 | biostudies-arrayexpress

2014-01-01 | GSE34228 | GEO

Phosphopattern Predicts CK2 Substrate, HMGA1, as a Drug Resistant Target for Non-Small Cell Lung Cancer

Project description:Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib. Acquired resistance to EGFR-TKIs develops after prolonged treatments. Known mechanisms for EGFR-TKI resistance, including KRAS mutation, HER2 mutation, EGFR T790M mutation and MET gene amplification did not observe in the resistant cells, PC9/gef. The study was prompt to explore effective strategies against resistance to EGFR-TKIs in PC9/gef cells. Here, we used label-free quantitative mass spectrometry to globally profile the basal phosphoproteome and proteome of a panel of TKI sensitive PC9, TKI resistant PC9/gef and TKI dose-dependent PC9/gef NSCLC cell lines. For phosphorylation level, we identified 5844 phosphorylation sites from 4612 phosphopeptides of 1548 proteins. For protein level, we identified 3835 proteins. Most of the quantitatively change is from phosphorylation whereas most of the protein level is unchanged. Among these big datasets, there is a phosphopattern of phosphopeptides presented up-regulated in resistant cells but no response to further gefitinib treatment; we proposed this group could regulate drug resistance. By motif analysis, these phosphopeptides mapped to the corresponding kinases, CK2, as the drug resistant kinase. Network analysis showed that CK2 directed interacting with 10 proteins. Among these proteins, we found that HMGA1 is the substrate protein to CK2. By biochemical evidence, we discovered that CK2 could regulate cell death in TKI-resistant cells. Furthermore, we found that HMGA1 for the first time could be the potential drug resistant target to reverse the drug resistance in PC9/gef cells. The results provide new insights into HMGA1 as the drug resistant target through the cellular signaling networks associated with the TKI-induced drug resistant NSCLCs.

2018-05-08 | PXD000861 | Pride

Acquired resistance to mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling

Project description:To compare gene copy number in cell populations with acquired resistance to specified EGFR inhibitors to parental cell lines. The aim of the experiment was to determine whether gain or loss of copy number of particular genes was associated with resistance to particular EGFR inhibitors. Comparing gene copy number in PC9 parental cells to gene copy number in 5 cell populations resistant to AZD9291, 2 cell populations resistant to WZ4002, 2 cell populations resistant to afatinib and 4 cell populations resistant to gefitinib.

2015-04-14 | E-GEOD-59239 | biostudies-arrayexpress

Non-coding mechanisms of tolerance, persistence and resistance to EGFR inhibition in lung cancer [microRNA-seq]

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

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