Gene Expression Patterns that Predict Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancer Cell Lines and Human Lung Tumors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE31625 | GEO | 2011/09/01
SECONDARY ACCESSION(S): PRJNA145541
REPOSITORIES: GEO
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Project description:Global gene expression data were generated from cultured non small cell lung cancer cell lines (NSCLC), normalized using MAS 5.0, filtered and used to predict response of cells to EGFR inhibition Gene expression data from additional cell lines and tumors was used to validate the predictive algorithm Total RNA was prepared from NSCLC cell lines and applied to Affymetric U133 2.0 microarrays
2011-08-31 | E-GEOD-31625 | biostudies-arrayexpress
Project description:BackgroundIncreased focus surrounds identifying patients with advanced non-small cell lung cancer (NSCLC) who will benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). EGFR mutation, gene copy number, coexpression of ErbB proteins and ligands, and epithelial to mesenchymal transition markers all correlate with EGFR TKI sensitivity, and while prediction of sensitivity using any one of the markers does identify responders, individual markers do not encompass all potential responders due to high levels of inter-patient and inter-tumor variability. We hypothesized that a multivariate predictor of EGFR TKI sensitivity based on gene expression data would offer a clinically useful method of accounting for the increased variability inherent in predicting response to EGFR TKI and for elucidation of mechanisms of aberrant EGFR signalling. Furthermore, we anticipated that this methodology would result in improved predictions compared to single parameters alone both in vitro and in vivo.ResultsGene expression data derived from cell lines that demonstrate differential sensitivity to EGFR TKI, such as erlotinib, were used to generate models for a priori prediction of response. The gene expression signature of EGFR TKI sensitivity displays significant biological relevance in lung cancer biology in that pertinent signalling molecules and downstream effector molecules are present in the signature. Diagonal linear discriminant analysis using this gene signature was highly effective in classifying out-of-sample cancer cell lines by sensitivity to EGFR inhibition, and was more accurate than classifying by mutational status alone. Using the same predictor, we classified human lung adenocarcinomas and captured the majority of tumors with high levels of EGFR activation as well as those harbouring activating mutations in the kinase domain. We have demonstrated that predictive models of EGFR TKI sensitivity can classify both out-of-sample cell lines and lung adenocarcinomas.ConclusionThese data suggest that multivariate predictors of response to EGFR TKI have potential for clinical use and likely provide a robust and accurate predictor of EGFR TKI sensitivity that is not achieved with single biomarkers or clinical characteristics in non-small cell lung cancers.
| S-EPMC1660550 | biostudies-literature
Project description:Global gene expression data were generated from cultured non small cell lung cancer cell lines (NSCLC), normalized using MAS 5.0, filtered and used to predict response of cells to EGFR inhibition Gene expression data from additional cell lines and tumors was used to validate the predictive algorithm Total RNA was prepared from NSCLC cell lines and applied to Affymetric U133 2.0 microarrays
| S-ECPF-GEOD-31625 | biostudies-other
Project description:The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.
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Project description:Effect of type 1 diabetes (induced by streptozotocin 60 mg/kg) on lung gene expression. Wistar rats, male. At age 8 weeks control rats got IP buffer, diabetic rats got streptozotocin. At age 12 weeks animals were anesthetized and lungs removed. RNA was extracted with Trizol, and gene expression array analysis was performed using Affymetrix RAE 230A microarrays according to the directions from the manufacturer. Arrays were scanned using a Hewlett Packard Gene Array scanner, and analyzed with Affymetrix MAS 5.0 software. Expression levels reported are the output from the MAS software.
2014-04-22 | GSE15900 | GEO
Project description:Inhibitor trials in chondrocytes - MAS 5.0 normalization
| PRJNA114847 | ENA
Project description:EGFR mutations identify patients who are more likely to respond to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) than cytotoxic chemotherapy. The distinct success of the first-generation EGFR TKIs erlotinib and gefitinib has been accompanied by the observation that acquired resistance to these treatments develops after a median of 1 year of treatment. Newer, second-generation EGFR TKIs have been developed with the intent to delay or overcome acquired resistance by the broader inhibition of kinases (eg, HER2 and vascular endothelial growth factor receptor) and/or altering the interactions with EGFR through irreversibly binding to the kinase domain. This article discusses many of these agents (including afatinib, dacomitinib, XL647, AP26113, and CO-1686) which have the potential for greater efficacy compared with first-generation EGFR TKIs, and may also have clinical activity against other oncogenic mutations within the EGFR family, including HER2.
| S-EPMC3673302 | biostudies-literature
Project description:First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.
| S-EPMC4129529 | biostudies-literature
Project description:Cancer associated fibroblasts (CAFs) play important roles in the chemotherapeutic process, especially through influencing the resistance of tumor cells to molecular targeted therapy. Here we report the existence of a special subpopulation of patient-specific-CAFs that augment the sensitivity of EGFR gene mutation-positive lung cancer to the EGFR-tyrosine kinase inhibitor (EGFR-TKI), gefitinib. When cocultured with EGFR mutation positive lung cancer cells, these CAFs increased the apoptic effect of gefitinib on cancer cells, whereas, in the absence of gefitinib, they did not affect cancer cell viability. The assay using different single cell-derived clones demonstrated that the aforementioned sensitizing ability is clone-specific. Microarray analysis revealed that CD200 was expressed at much higher levels in this CAFs. Knocking down of CD200 expression deprived CAFs of their sensitizing potential, suggesting that CD200 is the functional molecule responsible for the effect. Immunohistochemical analysis of samples from patients receiving postoperative gefitinib treatment revealed that the individuals whose resected lung adenocarcinomas contained CD200-positive CAFs tended to have longer progression free survival of gefitinib when they recurred after surgery. These results suggest that CD200-positive CAFs can augment the sensitivity to EGFR-TKIs and may possess far reaching applications in the therapeutic use of EGFR-TKIs.
| S-EPMC5399371 | biostudies-literature
Project description:Aberrant activation of the hedgehog (Hh) signaling pathway has been implicated in the epithelial-to-mesenchymal transition (EMT) and cancer stem-like cell (CSC) maintenance; both processes can result in tumor progression and treatment resistance in several types of human cancer. Hh cooperates with the epidermal growth factor receptor (EGFR) signaling pathway in embryogenesis. We found that the Hh signaling pathway was silenced in EGFR-TKI-sensitive non-small-cell lung cancer (NSCLC) cells, while it was inappropriately activated in EGFR-TKI-resistant NSCLC cells, accompanied by EMT induction and ABCG2 overexpression. Upregulation of Hh signaling through extrinsic SHH exposure downregulated E-cadherin expression and elevated Snail and ABCG2 expression, resulting in gefitinib tolerance (P < 0.001) in EGFR-TKI-sensitive cells. Blockade of the Hh signaling pathway using the SMO antagonist SANT-1 restored E-cadherin expression and downregulate Snail and ABCG2 in EGFR-TKI-resistant cells. A combination of SANT-1 and gefitinib markedly inhibited tumorigenesis and proliferation in EGFR-TKI-resistant cells (P < 0.001). These findings indicate that hyperactivity of Hh signaling resulted in EGFR-TKI resistance, by EMT introduction and ABCG2 upregulation, and blockade of Hh signaling synergistically increased sensitivity to EGFR-TKIs in primary and secondary resistant NSCLC cells. E-cadherin expression may be a potential biomarker of the suitability of the combined application of an Hh inhibitor and EGFR-TKIs in EGFR-TKI-resistant NSCLCs.
| S-EPMC4778934 | biostudies-literature