Expression data from EGFR WT or EGFR mutant NSCLC with or without erlotinib
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE57156 | GEO | 2014/05/16
SECONDARY ACCESSION(S): PRJNA245807
REPOSITORIES: GEO
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Project description:Non-small cell lung cancers (NSCLCs) harboring activating EGFR mutants show dramatic responses to EGFR TKIs, such as erlotinib and geffitinib. However, nearly all patients show relapse within 1 year after initial treatment. We used microarrays to detail global gene expression changes in EGFR mutant cells vs. WT cells responding to erlotinib. 4 EGFR mutant and 4 WT NSCLC cells were treated with or without erlotinib for 24 hr, followed by RNA extraction and hybridization on Affymetrix microarrays.
2014-05-16 | E-GEOD-57156 | biostudies-arrayexpress
Project description:Human non-small-cell lung cancers (NSCLCs) harboring activating mutations in epidermal growth factor receptor (EGFR) frequently respond to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib. However, the responses are not durable, and the magnitude of tumor regression is variable, suggesting the existence of genetic modifiers of EGFR dependency in EGFR-mutant NSCLCs. Here, we applied a genome-wide CRISPR-Cas9 screening to identify genetic determinants of EGFR TKI sensitivity and uncovered both known and putative candidates. Specifically, we show that knockout of RIC8A, a guanine nucleotide exchange factor (GEF) essential for G-alpha protein activation, enhanced EGFR TKI-induced cell death and prevented acquired resistance. Mechanistically, we demonstrate that RIC8A is a potent positive regulator of the pro-survival YAP signaling pathway, activation of which rescued the EGFR TKI sensitizing phenotype resulting from RIC8A knockout. We also show that knockout of ARIH2, or other components in the Cullin-5 E3 ubiquitin ligase complex, conferred resistance to EGFR inhibition, in part by promoting nascent protein synthesis through METAP2. Together, these data uncover a spectrum of previously unidentified regulators of EGFR TKI sensitivity in EGFR-mutant NSCLC cells, providing insights into the heterogeneity of EGFR TKI treatment responses in EGFR-mutant NSCLCs.
2019-11-14 | PXD014198 | Pride
Project description:The receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs), such as erlotinib. Chromatin-modifying agents offer a novel therapy approach by sensitizing tumor cells to TKIs. The NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) and NCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation were quantified by WST-1 assay, apoptosis by Annexin V/7-AAD flow cytometry and histone marks (acH3, H3K4me1,-2,-3) by immunoblotting. Expectedly, the EGFR wt cell lines A549 and NCI-H460 were insensitive to the growth-inhibiting effect of single-agent erlotinib (IC50 70-100µM), compared to HCC827 (IC50 <0.02μM). Treatment with panobinostat diminished growth to <50% in both EGFR wt and <30% in HCC827 cells. The combination of both drugs significantly reduced proliferation by ≥70% in A549, >95% in HCC827, but not further in NCI-H460. Panobinostat alone induced differentiation and expression of p21WAF1/CIP1 and p53 in all three cell lines, with almost no further increase when combined with erlotinib. In contrast, combination treatment additively decreased pERK, pAKT and pEGFR in A549, and synergistically induced acH3 in both adenocarcinoma lines. Surprisingly, we also saw an induction of H3K4 methylation marks in all three cell lines. In conclusion, panobinostat synergistically sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. Since single-agent erlotinib has only modest clinical effects in adenocarcinoma EGFR wt patients, combination therapy with an HDACi might offer a promising therapy approach to extend this activity. Copy-number analysis of three NSCLC cell lines HCC827, A549 and NCI-H460 (in unicates) was performed according to protocol by Affymetrix Genome-Wide Human SNP-Array 6.0.
2014-12-03 | E-GEOD-63784 | biostudies-arrayexpress
Project description:Background: The receptor tyrosine kinase (RTK) EGFR is overexpressed and mutated in NSCLC. These mutations can be targeted by RTK inhibitors (TKIs) such as erlotinib. Chromatin-modifying agents may offer a novel therapeutic approach by sensitizing tumor cells to TKIs. Methods: The NSCLC cell lines HCC827 (EGFR mutant, adenocarcinoma), A549 (EGFR wt, adenocarcinoma) andNCI-H460 (EGFR wt, large cell carcinoma) were analyzed by SNP6.0 array. Changes in proliferation after panobinostat (LBH-589, PS) and erlotinib treatment were quantified by WST-1 assay and apoptosis by Annexin V/7-AAD flow cytometry. Abundance of target proteins and histone marks (acH3, H3K4me1/2/3) was determined by immunoblotting. Results: As expected, the EGFR wt cell lines A549 and NCI-H460 were quite insensitive to the growth-inhibitory effect of single-agent erlotinib (IC50 70-100 μM), compared to HCC827 (IC50 < 0.02 μM). PS treatment diminished growth to <50 % in both EGFR wt cells, and <30 % in HCC827. The combination of both drugs reduced proliferation by >95 % in HCC827, ≥70 % in A549, but not further in NCI-H460. PS alone induced differentiation and expression of p21WAF1/CIP1 and p53 and decreased CHK1 in all three cell lines, with almost no further effect when combined with erlotinib. In contrast, combination treatment additively decreased pEGFR, pERK, pAKT in A549, and synergistically induced acH3 in both adenocarcinoma lines. Surprisingly, we saw an induction of H3K4 methylation marks after erlotinib treatment in HCC827 (and to a lesser extent in A549) that was even further enhanced by combination with PS. Conclusion: We were able to show that PS synergistically sensitized lung adenocarcinoma cells to the antiproliferative effects of erlotinib. Since single-agent erlotinib has only modest clinical effects in lung adenocarcinoma EGFR wt patients, its combination with an HDACi might offer a promising therapy approach.
2014-12-03 | GSE63784 | GEO
Project description:Analysis of human, adult, dermal fibroblasts following treatment with 100nM or 1 uM of erlotinib, a tryrosine kinase inhibitor (TKI) that targets the epidermal growth factor receptor (EGFR) inhibiting EGFR activation and signaling. Erlotinib is widely used to effectively treat patients with advanced non-small cell lung cancer but treatment with erlotinib and other EGFR TKIs are associated with a painful skin rash. Results identified significantly differentially expressed genes in fibroblasts treated with erlotinib providing insight into how the drug alters the transcriptome in ways that may contribute to the TKI-related rash.
2019-01-01 | GSE106151 | GEO
Project description:Despite the role of epidermal growth factor receptor (EGFR) signaling in head and neck squamous cell carcinoma (HNSCC) development and progression, clinical trials involving EGFR tyrosine kinase inhibitors (TKIs) have yielded poor results in HNSCC patients. Mechanisms of acquired resistance to the EGFR TKI erlotinib was investigated by developing erlotinib-resistant HNSCC cell lines (Cal-27, SCC-25, FaDu, and SQ20B) and comparing their gene expression profiles with their parental erlotinib-sensitive HNSCC cell lines using microarray analyses. Subsequent pathway and network analyses displayed a significant upregulation in immune response pathways. Role of immune/inflammatory signaling in acquired resistance to erlotinib in HNSCC was investigated.
2014-10-07 | GSE62061 | GEO
Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC. Overall, we completed array CGH analysis on 4 tumor specimens from EGFR mutant, TKI-resistant patients. Three of these samples had transformed to SCLC and one remained NSCLC.
2015-01-30 | E-GEOD-64765 | biostudies-arrayexpress
Project description:The Epidermal Growth Factor Receptor (EGFR) regulates a diverse set of biological processes including cell growth, proliferation, and differentiation. Deregulation of the EGFR pathway has been implicated in a variety of human diseases including cancer. Gefitinib and erlotinib are tyrosine kinase inhibitors (TKIs) that have demonstrated clinical benefit for patients with Non-small cell lung cancer (NSCLC) and EGFR activating mutations. However, patients invariably acquire resistance to TKI treatment through a number of mechanisms. We utilized in vitro models of NSCLC with EGFR activating mutations and derived three isogenic cell lines with acquired resistance to gefitinib. We next studied genomewide mRNA expression in resistance and wild type cells and their effect in the reprogramming of pathways in lung cancer cell line models..
2017-06-02 | GSE95590 | GEO
Project description:The Epidermal Growth Factor Receptor (EGFR) regulates a diverse set of biological processes including cell growth, proliferation, and differentiation. Deregulation of the EGFR pathway has been implicated in a variety of human diseases including cancer. Gefitinib and erlotinib are tyrosine kinase inhibitors (TKIs) that have demonstrated clinical benefit for patients with Non-small cell lung cancer (NSCLC) and EGFR activating mutations. However, patients invariably acquire resistance to TKI treatment through a number of mechanisms. We utilized in vitro models of NSCLC with EGFR activating mutations and derived three isogenic cell lines with acquired resistance to gefitinib. We next studied genomewide mRNA expression in resistance and wild type cells and their effect in the reprogramming of pathways in lung cancer cell line models..
2017-06-02 | GSE95558 | GEO
Project description:The study was designed to identify the molecular changes that occur in EGFR mutant NSCLCs that become resistant to TKI by transforming to SCLC. Tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, they do not lead to cures, and, on average, relapse occurs after one year of continuous treatment. In a subset of patients, a fundamental histological transformation from NSCLC to small cell lung cancer (SCLC) is observed in the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of a cohort of tumor samples and cell lines derived from resistant EGFR mutant patients with SCLC transformation revealed that RB is lost in 100% of these cases, but rarely in those that remain NSCLC. Global changes in gene expression, including increased neuroendocrine marker expression and absence of EGFR expression, are observed in cancers that transformed to SCLC. Consistent with their genetic and epigenetic similarities to classical SCLC, cell lines derived from resistant EGFR mutant SCLC biopsies are substantially more sensitive to ABT-263 treatment compared to those derived from resistant EGFR mutant NSCLCs. Together, these findings suggest that despite developing initially as EGFR mutant adenocarcinomas, this subset of resistant cancers ultimately take on many of the molecular and phenotypic characteristics of classical SCLC.
2015-01-30 | GSE64765 | GEO