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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103352 | GEO | 2018/01/11

SECONDARY ACCESSION(S): PRJNA401843

REPOSITORIES: GEO

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Mechanisms of tolerance and resistance to EGFR inhibition in lung cancer [RNA-seq]

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

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

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

2016-07-01 | E-GEOD-75308 | biostudies-arrayexpress

MUSASHI-2 RNA binding protein confers resistance to an epidermal growth factor receptor-tyrosine kinase inhibitor Osimertinib in lung adenocarcinoma

Project description:Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the acquired resistance to EGFR-TKIs, even third generation Osimertinib, the patients suffer poor prognosis. The resistance mechanisms are still not fully understood. Here, we demonstrate that increased expression of MUSASHI-2 (MSI2), an RNA binding protein, is novel mechanisms for resistance to EGFR-TKIs. We found that after long-exposure of gefitinib, the first generation EGFR-TKI, lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to not only gefitinib but also Osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the top list of the stemness-related genes upregulated in the EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including expression levels of Nanog a core stemness factor. We demonstrate that knockdown of MSI2 restored sensitivity to Osimertinib or gefitinib in the EGFR-TKI-resistant cells to the similar levels of the parental cells in vitro. RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to Osimertinib or gefitinib in parental cells. Finally, knockdown of MSI2 greatly increased sensitivity to Osimertinib in vivo. Collectively, our findings provide proof-of-principle that targeting MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent emergence of acquired resistance.

2021-08-27 | GSE168280 | GEO

IL-8 Confers Acquired Resistance to EGFR Inhibitors through Regulating Stem Cell-like Properties in Lung Cancer

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

scRNAseq of EGFR-mut PC9 cells control or treated for 24h or 72h with osimertinib

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2021-07-19 | E-MTAB-9468 | biostudies-arrayexpress

3' UTR RNA-seq of CRISPR-edited human EGFR-mutant PC9 lung cancer cell lines after osimertinib treatment

Project description:Human EGFR-mutant lung adenocarcinoma cells (PC9) were engineered using CRISPRv2 systemt to knock-out MAVS or STING to assess impact on transcriptomic response following osimertinib treatment

2021-07-19 | E-MTAB-9885 | biostudies-arrayexpress

IL-8 Confers Acquired Resistance to EGFR Inhibitors through Regulating Stem Cell-like Properties in Lung Cancer

2015-08-12 | GSE60189 | GEO

The lncRNAs, circRNAs and mRNAs involved in gefitinib-resistance of PC9 cells

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

Apatinib preferentially inhibits Gefitinib-resistant lung cancer cells by inducing cell cycle arrest and inhibiting VEGFR signaling pathway

Project description:Targeted therapy for patients with EGFR mutations by tyrosine kinase inhibitors (TKIs) has provided a significant benefit to patients. However, gradually developed resistance to the therapy becomes a major challenge in clinical practice. Herein, we report that Apatinib, an anti-angiogenic drug, strongly and specifically inhibits Gefitinib-resistant cancer cells but not their parental sensitive cells. Gefitinib-resistant lung cancer cell line (PC9GR) was established from its parental sensitive line (PC9) with a traditional EGFR mutation after long time exposure to Gefitinib. The established PC9GR cells had over 250 fold increased resistance to Gefitinib than its sensitive parental PC9 cells. Apatinib demonstrated much stronger (~5 fold) growth inhibition on PC9GR cells than on PC9 and other lung cancer cell lines. This inhibition was mostly achieved through cell cycle rest in G1 phase as demonstrated by transcriptome and protein expression data. Oral intake of Apatinib in mouse model significantly inhibited establishment and growth of PC9GR implanted tumors. VEGFR2 phosphorylation in PC9GR tumors after Apatinib treatment was significantly reduced along with less micro-vessel formation. Apatinib may provide a benefit to patients with acquired resistance to TKI treatment.

2019-05-15 | GSE129221 | GEO

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