Activation of IGFBP7 Drives Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition in Lung Cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE122005 | GEO | 2019/02/07
REPOSITORIES: GEO
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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:In this study, we explored the mechanisms of hypoxia-induced EGFR TKI resistance in non-small cell lung cancer (NSCLC) harbored activating EGFR mutation. The NSCLC cell lines were exposed to normorxia or 1% oxygen for 4 weeks, and then we tested EGFR TKI sensitivity in normoxic and hypoxic NSCLC cell lines. In this microarray experiment, we used normoxic HCC827 and hypoxia-induced gefitinib resistant clones, C2-3 and C2-10. Those clones were selected with gefitinib treatment after the HCC827 were exposed to 1% oxygen for 4 weeks, and the HCC827 C2-3 and C2-10 clones were selected at random for this study.
2020-12-19 | E-MTAB-9452 | biostudies-arrayexpress
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 (0.5µM) 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
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
Project description:Activating mutations of EGFR have been characterized as important mechanisms for carcinogenesis in a subset of EGFR-dependent non-small cell lung cancers (NSCLC). EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, have dramatic clinical effects on EGFR-addicted lung cancers and are used as first-line therapy for EGFR-mutant tumors. However, eventually all tumors acquire secondary resistance to the drugs and progress. We established a model to better understand mechanisms of acquired resistance. NCI- HCC827 cells are EGFR-mutant and highly erlotinib-sensitive. In this study we exposed HCC827 cells to increasing concentrations of erlotinib and two highly erlotinib-resistant subclones were developed (ER3 and T15-2). In these subclones no acquired alterations of EGFR or MET were found. We hereby performed a gene expression microarray studies to understand changes that might explain mechanisms of resistance. Through these studies we demonstrated in one resistant clone (ER3) overexpression of AXL, a tyrosine kinase implicated in imatinib and lapatinib resistance. Gene expression profilings were measured in NSCLC cell line HCC827 and two erlotinib-resistant HCC827-originated sublines ER3 and T15-2.
2012-05-29 | E-GEOD-38310 | biostudies-arrayexpress
Project description:Purpose: Multiple mechanims have been proposed that lead to reduced effectiveness of EGFR tyrosine kinase inhibitors (TKIs) in lung cancer and yet resistance to osimertinib and gefitinib still remains a challenge in the clinic. The goals of this study are to identify key genes contributing to tolerance and resistance to EGFR inhibition. Methods: mRNA profiles of gefitinib and osimertinib tolerant cells in PC9 and HCC827 cells were generated by deep sequencing using Illumina. In addition, mRNA profiles of cells (AALE, PC9 and HCC827) overexpressing with miR-147b or miR-21 and mRNA profiles of cells (H1975 and PC9ER) with miR-147b and miR-21 knocking down were generated by deep sequencing. The mappable reads were aligned to the human transcripts using Bowtie2 and gene abundance was estimated using RSEM. Results: Upregulation of miR-147b and miR-21 expression is related to tolerance and resistance to gefitinib and osimertinib in lung cancer. The signaling pathways of transcripts by knocking down miR-147b or miR-21 in resistant cells (H1975 and PC9ER) and by overexpressing miR-147b or miR-21 in both sensistive cells (HCC827 and PC9) and immortalized lung epithelial cells (AALE) are consistent with the key signaling pathways shown in tolerant cells to gefitinib and osimertinib in HCC827 and PC9 cells (HCC827GTR/OTR vs HCC827 and PC9GTR/OTR vs PC9). Conclusions: Our work identifies key signaling pathways that mediate EGFR-TKI tolerance and resistance in lung cancer. Our study provides potential targets to improve the efficacy of EGFR-TKIs therapy in cancer pagtients.
2018-01-11 | GSE103350 | GEO
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:Activating mutations of EGFR have been characterized as important mechanisms for carcinogenesis in a subset of EGFR-dependent non-small cell lung cancers (NSCLC). EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, have dramatic clinical effects on EGFR-addicted lung cancers and are used as first-line therapy for EGFR-mutant tumors. However, eventually all tumors acquire secondary resistance to the drugs and progress. We established a model to better understand mechanisms of acquired resistance. NCI- HCC827 cells are EGFR-mutant and highly erlotinib-sensitive. In this study we exposed HCC827 cells to increasing concentrations of erlotinib and two highly erlotinib-resistant subclones were developed (ER3 and T15-2). In these subclones no acquired alterations of EGFR or MET were found. We hereby performed a gene expression microarray studies to understand changes that might explain mechanisms of resistance. Through these studies we demonstrated in one resistant clone (ER3) overexpression of AXL, a tyrosine kinase implicated in imatinib and lapatinib resistance.
2012-05-30 | GSE38310 | 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:Previous study has demonstrated that PC9/gef cells are resistant to gefitinib-induced aspoptosis. To investigate the regulators contributed to gefitinib resistance in lung cancer, we analyzed the gene expression profiles between PC9 and PC9/gef cells. Our results showed that IL-8 contributes to gefitinib resistance and cancer stemness. In contrast, IL-8 knockdown decreased stem-like characteristics and increased gefitinib-induced apoptosis in PC9/gef cells. RNAs extracted from gefitinib-sensitive PC9 cells and gefitinib-resistant PC9/gef cells were hybridized on Affymetrix microarrays. We tried to compare the differential gene expression profiles between PC9 and PC9/gef cells to identify the possible regulators in gefitinib resistance.
2015-08-12 | E-GEOD-60189 | biostudies-arrayexpress