Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we examined the expression of excision repair cross-complementation group 1 (ERCC1) protein in 90 completely resected lung cancer samples from patients who received adjuvant or neo-adjuvant platinum-based chemotherapy. Epidermal growth factor receptor (EGFR) was also studied in these samples. We also examined class III beta-tubulin protein expression in 50 patients treated with a platinum-based drug plus paclitaxel. Among 90 patients treated with platinum-based chemotherapy, the loss of ERCC1 protein expression was associated with a better prognosis (p=0.0068). The effect of ERCC1 expression on survival was not seen in a separate set of 59 patients who underwent curative resection but did not receive adjuvant chemotherapy. Among 50 patients treated with a platinum-based drug plus paclitaxel, loss of class III beta-tubulin protein expression was also associated with a better prognosis (p=0.0303). When combined, patients with a tumor that was negative for both ERCC1 and class III beta-tubulin had a significantly longer overall survival than those with a tumor that expressed either ERCC1 or class III beta-tubulin (p=0.0230). There was no relationship between the presence of an EGFR mutation and the patients' survival after the platinum-based chemotherapy. In conclusion, we found that the loss of ERCC1 and class III beta-tubulin protein expression were predictors of better survival in patients who received a platinum-based plus taxane chemotherapy.
Lung Cancer 2008 Oct
PMID:Expression of excision repair cross-complementation group 1 and class III beta-tubulin predict survival after chemotherapy for completely resected non-small cell lung cancer. 1839 30

Epidermal growth factor receptor (EGFR) mutations in lung cancer enhance tyrosine kinase activity and increase sensitivity to the EGFR tyrosine kinase inhibitor, gefitinib. Mutation analysis of the EGFR gene is therefore indispensable for predicting gefitinib response. We investigated a CA-repeat polymorphism in the EGFR gene related to EGFR mutations. Because an increasing number of CA-repeats at intron 1 of the EGFR gene has been reported to reduce transcription activity, we examined the relationship between EGFR mutations and this CA-repeat polymorphism. EGFR mutations at exon 19 were closely associated with shorter CA-repeat length in the shorter allele, but this was not the case for EGFR mutations at exons 18 or 21. Increased intrinsic EGFR mRNA expression in non-cancerous lung tissues from lung adenocarcinoma patients was also significantly associated with shorter CA-repeat length. A higher frequency of EGFR mutations at exon 19 was associated with shorter CA-repeat length only in patients with high levels of EGFR mRNA expression. To determine the phenotypes of cells possessing shorter CA-repeats, an in vitro study using human bronchial epithelial cells with different CA-repeat lengths was performed; more rapid cell growth and activated EGF/EGFR signaling were found more often in the cells having both shorter CA-repeats and increased EGFR mRNA expression. These results suggest that CA-repeat length in the EGFR gene may be a genetic factor related to cancer in the case of EGFR mutations at exon 19. The mechanism likely involves enhanced intrinsic expression of EGFR mRNA and activated EGF/EGFR signaling that accompany shorter CA-repeats.
 ...
PMID:Exon 19 of EGFR mutation in relation to the CA-repeat polymorphism in intron 1. 1842 39

Since the late 1980s, lung cancer incidence in men has declined in Germany whereas in women there is still a rise. There is no approved screening program for lung cancer up to now and results from randomized trials like the National Lung Screening Trial are eagerly awaited. In stage II and IIIA non-small cell lung cancer (NSCLC), several positive trials have demonstrated the advantage of adjuvant chemotherapy which is now an established modality to improve cure rates. Epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC. Erlotinib, an EGFR tyrosine kinase inhibitor, has been approved for relapsed advanced-stage NSCLC. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor, a primary mediator of angiogenesis that is commonly overexpressed in solid tumors including lung cancer. Bevacizumab, in combination with chemotherapy, has demonstrated improved outcomes in advanced NSCLC and is now approved for selected patients with advanced-stage NSCLC. Patient selection for therapeutic use of bevacizumab is crucial to optimize safety. Ongoing trials explore multitargeted agents such as sorafenib, sunitinib, and vandetanib.
 ...
PMID:[Lung cancer]. 1848 17

Malignant pleural effusions (MPEs) are often observed in lung cancer, especially adenocarcinoma. Epidermal growth factor receptor (EGFR) gene mutations are usually detected in lung adenocarcinoma. The purpose of the present study was to investigate the EGFR mutation rate in MPEs of lung adenocarcinoma. Between June 2005 and December 2006, 136 MPEs from lung adenocarcinoma were collected for EGFR mutation detection. In addition, between April 2001 and November 2004, 91 surgically resected specimens of lung adenocarcinoma from patients without MPEs were assessed for EGFR mutation. The EGFR mutation rate was significantly higher in the patients with MPEs than in the patients without (68.4% versus 50.5%). The EGFR mutation rate in patients with MPEs was not associated with sex, smoking history, age or cancer stage. By multivariate analysis, an age of <65 yrs, never smoking, Eastern Cooperative Oncology Group performance status 0-1, and EGFR mutation were significantly associated with a longer overall survival for lung adenocarcinoma patients with MPEs. The patients with malignant pleural effusions related to lung adenocarcinoma had a higher epidermal growth factor receptor gene mutation rate than the patients from whom surgically resected specimens were taken. Epidermal growth factor receptor tyrosine kinase inhibitors may be the treatment of choice for lung adenocarcinoma with malignant pleural effusions in east Asia.
 ...
PMID:Frequent epidermal growth factor receptor gene mutations in malignant pleural effusion of lung adenocarcinoma. 1850 16

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib shows potent antitumor activity in some non-small-cell lung cancer (NSCLC) cell lines and is approved by the Food and Drug Administration as second and third line treatment for NSCLC. However, the molecular mechanisms by which erlotinib induces apoptosis remain to be elucidated. Here, we investigated the effect of erlotinib on apoptotic signal pathways in H3255 cells with the EGFR(L858R) mutation. Erlotinib induces apoptosis associated with the activation of caspases in a dose- and time-dependent manner. Erlotinib did not alter the expression of apoptotic receptors FAS and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although it induced caspase-8 activation and BID cleavage. In addition, cell death caused by erlotinib was not prevented by coincubation with FAS and TRAIL antagonists, ZB-4 monoclonal antibody and TRAIL/Fc recombinant, suggesting that erlotinib-induced apoptosis is not associated with receptor-mediated pathways. Erlotinib induces loss of mitochondrial membrane potential and release of cytochrome c and second mitochondria-derived activator of caspases/direct IAP binding protein with low pI from mitochondria. Furthermore, erlotinib causes BAX translocation to mitochondria, BAX and BAK conformational changes, and oligomerization. Erlotinib did not induce reactive oxygen species generation, and cotreatment with antioxidants did not alter erlotinib-induced activation of BAX and BAK and apoptosis. However, cotreatment with inhibitors of mitochondrial oxidative phosphorylation significantly blocked erlotinib-induced activation of BAX and BAK and cell death. Benzyloxycarbiny-VAD-fluoromethyl ketone had no effect on erlotinib-induced BAX and BAK activation but effectively prevented apoptosis. Overexpression of BCL-2 caused a significant attenuation of erlotinib-induced cell death, but no effect on BAX and BAK activation. Down-regulation of BAX and BAK gene expression with small interfering RNA led to an effective reduction of erlotinib-induced apoptosis. Our data indicate that activation of BAX and BAK plays a critical role in the initiation of erlotinib-induced apoptotic cascades.
 ...
PMID:Erlotinib induces mitochondrial-mediated apoptosis in human H3255 non-small-cell lung cancer cells with epidermal growth factor receptorL858R mutation through mitochondrial oxidative phosphorylation-dependent activation of BAX and BAK. 2613 Feb 90

Epidermal growth factor receptor (EGFR) is activated by ionizing radiation (IR), but the molecular mechanism for this effect is unknown. We have found that intracellular generation of nitric oxide (NO) by NO synthase (NOS) is required for the rapid activation of EGFR phosphorylation by IR. Treatment of A549 lung cancer cells with IR increased NOS activity within minutes, accompanied by an increase of NO. 2-Phenyl-4,4,5,5,-tetramethylimidazolline-1-oxyl-3-oxide, an NO scavenger, and NG-monomethyl-l-arginine, an NOS inhibitor, abolished the increase in intracellular NO and activation of EGFR by IR. In addition, an NO donor alone induced EGFR phosphorylation. Transient transfection with small interfering RNA for endothelial NOS reduced IR-induced NO production and suppressed IR-induced EGFR activation. Overexpression of endothelial NOS increased IR-induced NO generation and EGFR activation. These results indicate a novel molecular mechanism for EGFR activation by IR-induced NO production via NOS.
 ...
PMID:Activation of epidermal growth factor receptor and its downstream signaling pathway by nitric oxide in response to ionizing radiation. 1856 3

Epidermal growth factor receptor signaling pathway plays an important role in pulmonary adenocarcinoma biology. Targeted therapy with tyrosine kinase inhibitors like gefitinib and erlotinib are being used in selected patients with variable response rates. Several RCT and other studies have evaluated the value of various tests such as immunohistochemistry, polymerase chain reaction, and fluorescent in situ hybridization for epidermal growth factor receptor detection. The clinical validity and applicability of these tests remain controversial. Evidence-based pathology promotes the use of systematic review of the literature and meta-analysis rather than subjective appraisal of the literature. We performed a systematic review of the literature to identify the "best evidence" regarding the use of these tests. The data were analyzed using Comprehensive meta-analysis software (Biostat, Inc, Englewood, NJ). Most of the information regarding epidermal growth factor receptor tests has been published in retrospective case series with few double-blind and prospective RCT. Estimated positive predictive values of immunohistochemistry, polymerase chain reaction, and fluorescent in situ hybridization range from 6.5% to 82%%, 7% to 100%, and 11% to 89%, respectively. Meta-analysis of nearly 5000 cases in the literature estimates that all 3 tests significantly predict response to gefitinib in patients with lung cancer. It shows lack of heterogeneity within the study results, although the current best evidence is limited by variations in study methodologies, patient ethnicity, test interpretation criteria, and variable definitions of treatment response. There is only one study evaluating the value of epidermal growth factor receptor tests in predicting response to erlotinib. Further studies are needed to clarify the predictive value of epidermal growth factor receptor tests in patients with pulmonary adenocarcinoma.
 ...
PMID:The predictive value of epidermal growth factor receptor tests in patients with pulmonary adenocarcinoma: review of current "best evidence" with meta-analysis. 1897 96

Epidermal growth factor receptor (EGFR) plays an important role in the development and progression of a variety of malignant tumors. To test single nucleotide polymorphisms (SNPs) and haplotypes of the EGFR in modulating the lung cancer susceptibility, we conducted a matched case-control study of 730 lung cancer patients and 730 healthy controls for examining the association in Taiwanese population. Fourteen tag SNPs distributed in EGFR were selected for genotyping and one SNP 8227G>A (rs763317) located in the intron 1 of EGFR was significantly associated with lung cancer (P=0.009). Interestingly, the increase of lung cancer risk is significantly associated with never-smoking female adenocarcinoma patients harboring 8227A allele. In never-smoking female population, ORs for 8227G>A were significantly increased in adenocarcinoma subtype (adjusted odds ratio (OR) for GA genotype=1.23, 95% confidence interval (CI)=0.87-1.75; and adjusted OR for AA genotype=3.52, 95% CI=1.32-9.37, respectively). The ORs in dominant or recessive genetic model were also significantly increased in female lung adenocarcinoma subtype (adjusted OR=1.35, 95% CI=1.05-1.90; and adjusted OR=3.26, 95% CI=1.24-8.62, respectively). Haplotype analyses of 14 EGFR SNPs revealed that haplotype comprising the rare allele of 8227G>A and the common allele of the other 13 SNPs was associated with a significantly increased risk of female adenocarcinoma (OR=2.81, 95% CI=1.02-7.77). Together, our results suggest that polymorphisms or haplotypes of the EGFR play an important role in the development of lung cancer in Taiwan, particularly in never-smoking female lung adenocarcinoma.
Lung Cancer 2009 Jun
PMID:Association of an EGFR intron 1 SNP with never-smoking female lung adenocarcinoma patients. 1902 60

Targeted therapies have improved and will continue to improve the outcome of lung cancer. Current strategies focus on the blockade of growth factor receptors and the inhibition of angiogenesis. Epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) have already been established as a treatment option in patients with advanced non-small cell lung cancer (NSCLC) progressing after prior treatment with chemotherapy. EGFR-directed monoclonal antibodies in combination with platinum-based first-line chemotherapy have shown promising efficacy in phase II trials. In a phase III trial, cetuximab combined with cisplatin/vinorelbine resulted in superior survival compared to chemotherapy alone in patients with advanced EGFR-positive NSCLC. Inhibition of angiogenesis has also been successfully applied as a new treatment strategy. Bevacizumab added to palliative chemotherapy has improved progression-free survival in two phase III trials and overall survival in one of these trials in selected patients with advanced non-squamous cell lung cancer. Bevacizumab is now approved for selected patients with advanced NSCLC in combination with platinum-based chemotherapy. Other targeted therapies including dual and multi-kinase inhibitors are in earlier stages of clinical development. In small cell lung cancer (SCLC), targeted therapies have also been studied but no clinical benefit could be demonstrated for these agents.
 ...
PMID:Targeted therapies in lung cancer. 1914 12

In non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) and K-RAS mutations of the primary tumour are associated with responsiveness and resistance to tyrosine kinase inhibitors (TKIs), respectively. However, the EGFR and K-RAS mutation status in metastases is not well studied. We compared the mutation status of these genes between the primary tumours and the corresponding metastases of 25 patients. Epidermal growth factor receptor and K-RAS mutation status was different between primary tumours and corresponding metastases in 7 (28%) and 6 (24%) of the 25 patients, respectively. Among the 25 primary tumours, three 'hotspot' and two non-classical EGFR mutations were found; none of the corresponding metastases had the same mutation pattern. Among the five (20%) K-RAS mutations detected in the primary tumours, two were maintained in the corresponding metastasis. Epidermal growth factor receptor and K-RAS mutations were detected in the metastatic tumours of three (12%) and five (20%) patients, respectively. The expressions of EGFR and phosphorylated EGFR showed I 0 and 50% discordance, in that order. We conclude that there is substantial discordance in EGFR and K-RAS mutational status between the primary tumours and corresponding metastases in patients with NSCLC and this might have therapeutic implications when treatment with TKIs is considered.
 ...
PMID:Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC. 1923 33


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>