Egfr
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Egfr -Epidermal growth factor receptor
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To re-treat or not with gefitinib/erlotinib: This is the question for tyrosine kinase inhibitor-responsive lung cancers that progress.
Journal: Lung cancer (Amsterdam, Netherlands)
October/17/2007
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Pubmed
Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment.
Journal: Annals of oncology : official journal of the European Society for Medical Oncology
September/1/2017
Description

UNASSIGNED

The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.

UNASSIGNED

We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).

UNASSIGNED

In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.

UNASSIGNED

T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

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Pubmed
Co-targeting of EGF receptor and neuropilin-1 overcomes cetuximab resistance in pancreatic ductal adenocarcinoma with integrin β1-driven Src-Akt bypass signaling.
Journal: Oncogene
September/6/2017
Description

Pancreatic ductal adenocarcinoma (PDAC) cells usually overexpress the epidermal growth factor receptor (EGFR); however, most are resistant to the anti-EGFR monoclonal antibody, cetuximab. In this study, we report that the molecular mechanism of resistance to cetuximab in PDAC cells is mediated by the overexpression of active integrin β1 with downstream Src-Akt activation; this triggers an EGFR ligand-independent proliferation signaling, bypassing EGFR-blocking effect. Knockdown of integrin β1 or inhibition of Src or Akt sensitized cetuximab-resistant (CtxR) PDAC cells to cetuximab. We found that neuropilin-1 (NRP1) physically interacts with active integrin β1, but not inactive one, on the cell surface. To inhibit active integrin β1-driven signaling by targeting NRP1, while suppressing EGFR signaling, we generated an EGFR and NRP1 dual targeting antibody, Ctx-TPP11, by genetic fusion of the NRP1-targeting peptide, TPP11, to the C terminus of the cetuximab heavy chain (Ctx-TPP11). We demonstrate that Ctx-TPP11 efficiently inhibited the growth of CtxR PDAC cells, in vitro and in vivo. The sensitization mechanism involved downregulating active integrin β1 levels through NRP1-coupled internalization mediated by the TPP11 moiety, leading to the inhibition of active integrin β1-driven bypass signaling. Our findings identify aberrant active integrin β1-driven Src-Akt hyperactivation as a primary resistance mechanism to cetuximab in PDAC cells and offer an effective therapeutic strategy to overcome this resistance using an EGFR and NRP1 dual targeting antibody.

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Pubmed
Argos mutants define an affinity threshold for spitz inhibition in vivo.
Journal: The Journal of biological chemistry
November/26/2006
Description

Argos, a secreted antagonist of Drosophila epidermal growth factor receptor (dEGFR) signaling, acts by sequestering the activating ligand Spitz. To understand how different domains in Argos contribute to efficient Spitz sequestration, we performed a genetic screen aimed at uncovering modifiers of an Argos misexpression phenotype in the developing eye. We identified a series of suppressors mapping to the Argos transgene that affect its activity in multiple developmental contexts. These point mutations map to both the N- and C-terminal cysteine-rich regions, implicating both domains in Argos function. We show by surface plasmon resonance that these Argos mutants are deficient in their ability to bind Spitz in vitro. Our data indicate that a mere approximately 2-fold decrease in K(D) is sufficient to compromise Argos activity in vivo. This effect could be recapitulated in a cell-based assay, where a higher molar concentration of mutant Argos was needed to inhibit Spitz-dependent dEGFR phosphorylation. In contrast, a approximately 37-fold decrease in the binding constant nearly abolishes Argos activity in vivo and in cellular assays. In agreement with previously reported computational studies, our results define an affinity threshold for optimal Argos inhibition of dEGFR signaling during development.

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Pubmed
Overexpression of transglutaminase in the Drosophila wing imaginal disc induced an extra wing crossvein phenotype.
Journal: Bioscience, biotechnology, and biochemistry
March/27/2011
Description

To determine the roles of Drosophila transglutaminase-A (dTG-A), we examined a phenotype induced through ectopic expression of dTG-A. Overexpression of dTG-A in the wing imaginal disc induced an extra wing crossvein phenotype. This phenotype was suppressed by crossing with epidermal growth factor receptor (Egfr) signaling pathway mutant flies. These results indicate that this phenotype, induced by dTG-A, is related to enhancement of the Egfr signaling pathway.

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Pubmed
Expression and mutation analysis of EGFR, c-KIT, and β-catenin in pulmonary blastoma.
Journal: Journal of clinical pathology
August/16/2011
Description

BACKGROUND

Pulmonary blastoma (PB) is a rare malignant lung tumour with an immature mesenchymal and epithelial component resembling fetal lung. In order to define potential therapeutic targets in PB, the authors analysed the status and possible role of EGFR, HER2 and c-KIT in the pathogenesis of this tumour type, and the diagnostic value of β-catenin mutation analysis in PB.

METHODS

5 PBs were analysed for EGFR, HER2, c-KIT, and β-catenin expression, as well as for mutations in EGFR, c-KIT, k-ras and the β-catenin gene (CTNNB1).

RESULTS

EGFR expression was observed in all PBs. An EGFR mutation was found in one of the tumours. No overexpression of c-KIT or HER2 was seen. No mutations were found in k-ras or c-KIT. 3 of 5 PBs displayed CTNNB1 mutations. Nuclear translocation of β-catenin was seen in 2 of these tumours.

CONCLUSIONS

Detection of EGFR expression and mutation in PB suggest EGFR inhibition as a potential therapeutic option in the treatment of advanced PB. Moreover, the data confirm a crucial role of CTNNB1 mutations in the pathogenesis of PB, and indicate that CTNNB1 gene sequencing may be a useful in distinguishing PB from other types of lung cancer.

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Pubmed
Expression of p16 protein and epidermal growth factor receptor in patients with adenocarcinoma of the uterine cervix: an immunohistochemical analysis.
Journal: Archives of gynecology and obstetrics
June/23/2011
Description

OBJECTIVE

The present study assessed the expression of p16 and epidermal growth factor receptor (EGFR) in patients with adenocarcinoma of the uterine cervix to determine their influence on prognosis and to evaluate a possible association between their expression and various clinicopathologic parameters.

METHODS

p16 and EGFR expression was investigated by immunohistochemistry from paraffin-embedded tissue in 39 patients with adenocarcinoma of the uterine cervix. The immunohistochemical findings were correlated with different clinicopathologic parameters of the patients.

RESULTS

p16 was expressed in 56% of the patients. A trend towards increased lymph vascular space invasion was observed in p16 positive tumors (p = 0.06). There was no statistically significant association between p16 expression and clinical stage, age, histology, tumor size, tumor grade, lymph node status and recurrence disease (p > 0.05). p16 expression did influence neither disease-free nor overall survival (p > 0.05). EGFR was expressed in 44% of the patients. There was no statistically significant correlation between EGFR expression and clinical stage, age, histology, tumor size, tumor grade, lymph vascular space invasion, lymph node status and recurrence disease (p > 0.05). EGFR expression did influence neither disease-free nor overall survival (p > 0.05).

CONCLUSIONS

p16 and EGFR are frequently expressed in adenocarcinoma of the uterine cervix. Our study observed a trend towards increased lymph vascular space invasion in p16 positive tumors. Otherwise, the expression of the investigated parameters did not correlate with any clinicopathologic parameters and had no influence on overall and disease-free survival. So far, the investigation of p16 and EGFR is of limited use to assess patients' prognosis and guide clinical management.

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Pubmed
Correlation of epidermal growth factor receptor mutation, immunohistochemistry, and fluorescence in situ hybridization in esophageal squamous cell carcinoma.
Journal: Journal of the Medical Association of Thailand = Chotmaihet thangphaet
November/30/2009
Description

BACKGROUND

The epidermal growth factor receptor (EGFR) has become a promising target for novel anticancer therapy Evaluation of its biological profiles including gene mutation, amplification, and protein expression in esophageal squamous cell carcinoma (ESCC) is essential to establish the EGFR molecular feature(s) suitable to select patients in anti-EGFR therapy.

METHODS

The subjects' specimens of ESCC at Songklanagarind Hospital were obtained and investigated for EGFR protein expression and gene amplification. Polymerase chain reaction (PCR) was performed to amplify the EGFR DNA product. The mutational status of EGFR exons 19 and 21 was analyzed using direct sequencing. The entire biological profiles of the EGFR were then correlated.

RESULTS

There were 48 eligible ESCC specimens. No somatic mutation in the tyrosine kinase domain of EGFR was detected A high level of EGFR protein was exhibited in 22 patients (46%). Twenty-three patients (48%) had shown a high gene copy numbers. However, no direct correlation between EGFR protein and gene status was observed.

CONCLUSIONS

EGFR mutations in the tyrosine kinase domain of exons 19 and 21 were absent in ESCC, whereas, protein overexpression and gene amplification was prevalent. Therefore, selection of ESCC patients for studies with anti-EGFR agents based on protein expression or gene copy number, not gene mutation, is rational.

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Pubmed
Relationship between expression of EGFR in gastric cancer tissue and clinicopathological features.
Journal: Asian Pacific journal of tropical medicine
October/16/2013
Description

OBJECTIVE

To investigate the relationship between the expression of epidermal growth factor receptor (EGFR) in gastric cancer and the clinicopathological features and prognosis.

METHODS

A total of 78 paraffin specimens of gastric cancer operation were collected. The immunohistochemical method was used to detect the expression of EGFR in 78 cases of gastric cancer and 20 cases of adjacent normal tissue. The relationship between the high expression of EGFR and clinicopathological features was analyzed.

RESULTS

EGFR positive expression rate in the 78 cases of gastric cancer tissue was 57.7 % (45/78), while EGFR was not expressed in 20 cases of adjacent normal tissue. The high EGFR expression was positively correlated with the position of gastric cancer, tumor size, cell differentiation, invasive depth, lymph node metastasis and TNM staging, yet having no obvious relation with gender or age.

CONCLUSIONS

EGFR expression level in gastric cancer is closely related to the incidence and development of gastric cancer, which can provide a theoretical basis for the targeted therapy for gastric cancer with EGFR as the target.

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Pubmed
[Relationship between the expression of hypoxia-inducible factor-1alpha and epidermal growth factor receptor and micro vessel density and their clinical significance].
Journal: Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery
April/10/2011
Description

OBJECTIVE

Analyze the relationship between the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and epidermal growth factor receptor (EGFR) and CD105 micro vessel density (MVD) and their value in evaluating biologic behavior and prognosis in laryngeal cancer.

METHODS

Ninety-one cases of laryngeal cancer were analyzed about their clinical and pathology data. In tumor tissue the expression of HIF-1alpha and EGFR was detected by immunohistochemistry and MVD was marked by CD105.

RESULTS

The expression of HIF-1alpha was correlated with size, TNM stage, T stage, lymph node metastasis and histological grade (all P<0.05). The expression of EGFR was correlated with TNM stage, lymph node metastasis, histological grade and relapse (all P<0.05). MVD was correlated with type, TNM stage, T stage, lymph node metastasis, metastasis and histological grade (all P<0.05). The expression of HIF-1alpha and EGFR was correlated with MVD (F value was 7.644 and 5.197 respectively, P value was 0.001 and 0.025 respectively). The correlation between the expression of HIF-1alpha and EGFR was significant statistically (r= 0.238, P=0.007). The survival rate of patients of 3 years and 5 years were 56.1% and 44.2% respectively. Survival analysis by Log Rank showed that prognosis of laryngeal cancer patients was correlated with type, TNM stage and the expression of both HIF-1alpha and EGFR. While Cox multiple factors analysis demonstrated that TNM stage and expression of EGFR were independent prognostic factor of laryngeal cancer (P value was 0.049 and 0.041 respectively, RR was 1.300 and 2.417 respectively).

CONCLUSIONS

HIF-1alpha and EGFR are key molecular event during development and progression of laryngeal cancer, which act in regulating tumor angiogenesis as well, and show intimate relationship with biological behavior and prognosis of laryngeal cancer.

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