Gene Expression Regulation by Lung Cancer Oncogenes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE104494 | GEO | 2017/10/03
SECONDARY ACCESSION(S): PRJNA412863
REPOSITORIES: GEO
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Project description:Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). TKI responses vary across tumors driven by the heterogeneous group of exon 19 deletions and mutations, but the molecular basis for these differences is not understood. We characterized the dynamics of the selected EGFR exon 19 mutants by HDX-MS to study the molecular basis of TKI sensitivity and tolerance.
2023-03-11 | PXD037355 | Pride
Project description:We analyzed mutations in Epidermal Growth Factor Receptor (EGFR) Tyrosine kinase (TK) domain, EGFR expression and gene profiling in prostate carcinoma (PC) in order to find out molecular prognostic markers and supply a proof for EGFR targeted therapies. 100 glyofixx-fixed, paraffin-embedded PC specimens were recovered after radical prostatectomy from locally advanced PC patients. Exons from 18 to 21 of EGFR TK domain were amplified and sequenced. For the entire cohort, EGFR protein evaluation by immunohistochemistry was performed. Gene expression profile was analyzed on 51 out of 100 samples by whole genome microarray. Statistical tests were performed in order to detect any significant association between EGFR iperexpression and prognosis. None out of 100 specimens presented mutations in exon 18; 2 point mutations were identified in exon 19, 5 in exon 20 and 6 in exon 21. In addiction, 58 out of 100 patients had the same silent mutation, at codon 787 in exon 20. EGFR iper-expression was found in 36% of specimens and was significantly associated with biochemical relapse. Gene profiling analysis on mutated samples selected 29 modulated genes differentially expressed between mutated EGFR+ and mutated EGFR- samples; 4 down-regulated genes, EAF2, ABCC4, KLK3 and ANXA3 and one up-regulated gene, FOXC1, are involved in prostate cancer progression. Our findings suggest that a subgroup of PC patients could potentially benefit of EGFR targeted therapies. The EGFR protein evaluation could contribute to identify PC relapsers. Keywords: EGFR expression, TK mutations, target therapy, microarray data. In this work we studied mutation status and expression of Epidermal Growth Factor Receptor (EGFR) in a case series of 100 primary prostate cancer tissue specimens. Results indicate that 13% and 36% of PC patients presents EGFR tyrosine kinase domain mutations and iperexpression respectively, suggesting that this receptor could be a therapeutic target in progressive prostate cancer. The analysis of correlation between EGFR protein expression, mutations, clinical parameters and outcome allow us to identify EGFR as significantly associated with biochemical relapse and high Gleason score. Gene expression profiling in 51 of PC tissues led to the identification of a gene list which separated EGFR mutated patients according to EGFR protein expression. These results could give more information on clinical outcome and possible development of new targeted therapies.
2011-06-30 | E-GEOD-16120 | biostudies-arrayexpress
Project description:The cell surface proteome, the surfaceome, is the interface for engaging the extracellular space in normal and cancer cells. Here we apply quantitative proteomics of N-linked glycoproteins to reveal how a collection of some 700 surface proteins is dramatically remodeled in an isogenic breast epithelial cell line stably expressing any of six of the most prominent proliferative oncogenes, including the receptor tyrosine kinases, EGFR and HER2, and downstream signaling partners such as KRAS, BRAF, MEK and AKT. We find that each oncogene has somewhat different surfaceomes but the functions of these proteins are harmonized by common biological themes including up-regulation of nutrient transporters, down-regulation of adhesion molecules and tumor suppressing phosphatases, and alteration in immune modulators. Addition of a potent MEK inhibitor that blocks MAPK signaling brings each oncogene-induced surfaceome back to a common state reflecting their strong dependence on the MAPK pathway to propagate signaling. Using a recently developed glyco-proteomics method of activated ion electron transfer dissociation (AI-ETD) we found massive oncogene-induced changes in 142 N-linked glycans and differential increases in complex hybrid glycans especially for KRAS and HER2 oncogenes. Overall, these studies provide a broad systems level view of how specific driver oncogenes remodel the surface glycoproteome in a cell autologous fashion, and suggest possible surface targets, and combinations thereof, for drug and biomarker discovery.
2020-04-08 | PXD017039 | Pride
Project description:Tyrosine kinase inhibitors (TKIs) are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). We studied structural basis of differential TKI sensitivity among EGFR exon 19 mutants by HDX-MS.
2023-03-11 | PXD037374 | Pride
Project description:Tyrosine kinase inhibtors are used to treat non-small cell lung cancers (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain (TKD). We characterized the dynamics of purified EGFR exon 19 kinase domain mutants by HDX-MS with or withour erlotinib, one of the first-generation TKIs.
2023-03-11 | PXD037448 | Pride
Project description:Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been recommended as the first line therapy for non-small cell lung cancer (NSCLC) with EGFR mutations. However, acquired resistance to EGFR-TKIs is inevitable. Although anti- programmed cell death 1 (PD-1)/PD-ligand (PD-L1) immunotherapies have achieved great clinical success as second-line treatment for many cancer types, the clinical efficacy of anti-PD-1/PD-L1 blockades in EGFR mutated NSCLC patients has been demonstrated to be obviously lower than those without EGFR mutations. Here, we reported an advanced NSCLC patient with exon 19 deletion and T790M EGFR mutation benefitting from anti-PD-1 blockade therapy after acquiring resistance to EGFR-TKI. We characterized the mutational landscape of the patient with next-generation sequencing (NGS), and successfully identified neoantigen-specific T cell clones derived from EGFR exon 19 deletion, TP53 A116T and DENND6B R398Q mutations. Our findings support the potential application of immune checkpoint blockades in NSCLC patients with acquired resistance to EGFR-TKIs in the context of specific clonal neoantigens with high immunogenicity. Personalized immunomodulatory therapy targeting these neoantigens should be explored for better clinical outcomes in EGFR mutant NSCLC patients.
2020-06-30 | GSE150972 | GEO
Project description:Identification and Functional Analysis of Novel Oncogenes in Pancreatic Ductal Adenocarcinoma
| PRJNA719796 | ENA
Project description:We analyzed mutations in Epidermal Growth Factor Receptor (EGFR) Tyrosine kinase (TK) domain, EGFR expression and gene profiling in prostate carcinoma (PC) in order to find out molecular prognostic markers and supply a proof for EGFR targeted therapies. 100 glyofixx-fixed, paraffin-embedded PC specimens were recovered after radical prostatectomy from locally advanced PC patients. Exons from 18 to 21 of EGFR TK domain were amplified and sequenced. For the entire cohort, EGFR protein evaluation by immunohistochemistry was performed. Gene expression profile was analyzed on 51 out of 100 samples by whole genome microarray. Statistical tests were performed in order to detect any significant association between EGFR iperexpression and prognosis. None out of 100 specimens presented mutations in exon 18; 2 point mutations were identified in exon 19, 5 in exon 20 and 6 in exon 21. In addiction, 58 out of 100 patients had the same silent mutation, at codon 787 in exon 20. EGFR iper-expression was found in 36% of specimens and was significantly associated with biochemical relapse. Gene profiling analysis on mutated samples selected 29 modulated genes differentially expressed between mutated EGFR+ and mutated EGFR- samples; 4 down-regulated genes, EAF2, ABCC4, KLK3 and ANXA3 and one up-regulated gene, FOXC1, are involved in prostate cancer progression. Our findings suggest that a subgroup of PC patients could potentially benefit of EGFR targeted therapies. The EGFR protein evaluation could contribute to identify PC relapsers. Keywords: EGFR expression, TK mutations, target therapy, microarray data.
2011-06-30 | GSE16120 | GEO
Project description:In the current study, we used exon arrays and clinical samples from a previous trial (SAKK 19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response (EGFR, KRAS, VEGFA). Exon-level biomarkers for the response to targeted therapy bevacizumab/erlotinib were identified in patients with metastatic non-small cell lung cancer
2013-07-30 | GSE37138 | 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