Ontology highlight
ABSTRACT:
PROVIDER: PRJNA831780 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the following subset Series: GSE37698: Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors (SNP array) GSE37699: Aberrant ERK signaling causes resistance to EGFR kinase inhibitors Refer to individual Series
2012-10-01 | E-GEOD-37700 | biostudies-arrayexpress
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.
2015-04-14 | GSE59239 | GEO
Project description:Lung adenocarcinoma PC9 cells were engineered to not only contain the driving EGFR-mutations, but also EGFR T790M and EGFR C797S that provide resistance to EGFR inhibitors.
2021-07-19 | E-MTAB-9887 | biostudies-arrayexpress
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
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.
2016-08-23 | GSE74575 | GEO
Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.
2012-10-01 | GSE37698 | GEO
Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Our study identifies ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. To generate drug-resistant NCI-H1975 cell lines, non-small cell lung cancer (NSCLC) cells were exposed to increasing concentrations of WZ4002 similar to previously described methods. Individual clones from WZ4002-resistant (WZR) cells were isolated and confirmed to be drug resistant. Clone #6, designated as WZR6, was used in this study. For expression analysis, samples were prepared in triplicate from parental NCI-H1975 and NCI-H1975 WZR6 cells.
2012-10-01 | E-GEOD-37699 | biostudies-arrayexpress
Project description:Aberrant ERK signaling causes resistance to EGFR kinase inhibitors
2015-08-19 | E-GEOD-37699 | ExpressionAtlas
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:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Our study identifies ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism.
2012-10-01 | GSE37699 | GEO