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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal growth factor receptor (EGFR) is highly expressed in many human tumors including non-small cell lung cancer (NSCLC). Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has led to dramatic clinical improvement in selected patients with NSCLC. However, intrinsic and acquired resistance to EGFR-TKI remains a common phenomenon. Novel EGFR-TKI, structurally different with erlotinib or gefitinib might be beneficial for patients with NSCLC. In this study, we examined the anti-tumor effect of a newly synthesized novel EGFR tyrosine kinase inhibitor N-(3-chloro-4-fluorophenyl)-N-(7-methoxy-6-(3-morpholinopropoxy) quinazolin-4-yl)-3,3-dimethylbutanamide (F90). In vitro studies in a panel of three different human NSCLC cell lines revealed that F90 inhibited cell proliferation with high potency and induced G0/G1 arrest of cell cycle and apoptosis. F90 markedly reduced phosphorylation of EGFR and inhibited activation of MAPK and Akt. Oral administration of F90 (80mg/kg/day) to BALB/c nude mice bearing NSCLC cell lines xenografts significantly retarded tumor growth. In conclusion, F90 has potent anti-tumor activity on human lung cancer in vitro and in vivo.
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PMID:Anti-tumor activity of a novel EGFR tyrosine kinase inhibitor against human NSCLC in vitro and in vivo. 1929 77

Despite the advances in the detection and treatment of lung cancer, the overall 5-year survival is only 10-20%. Accumulating evidence suggests that verapamil, a calcium channel antagonist, is a potential anticancer agent. Epidermal growth factor receptor (EGFR) is a key therapeutic target in many types of cancer, whereas nm23 is a putative metastasis suppressor gene. In this study, the effect of verapamil on the expression of nm23 and EGFR in A549 human lung cancer cells was investigated by quantitative real-time reverse transcription-polymerase reaction and immunohistochemical assays. The expression of EGFR and nm23 was also determined in lung cancer patients. Verapamil significantly reduced EGFR expression at both the mRNA and protein levels in A549 cells (p < 0.01). Verapamil also significantly increased the protein levels of nm23 in these cells (p < 0.01), although the mRNA levels of nm23 were not changed after verapamil treatment. Furthermore, the expression of EGFR in human lung cancer tissues was significantly higher than in normal lung tissues (p < 0.001). However, the expression of nm23 was not different between lung cancer and normal tissues. Our data suggest that verapamil may regulate the expression of EGFR and nw23 in lung cancer cells by transcriptional and post-transcriptional levels, respectively. EGFR may be a promising therapeutic molecular target for lung cancer treatment using verapamil and/or chemotherapeutic agents.
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PMID:Effect of verapamil on the expression of EGFR and NM23 in A549 human lung cancer cells. 1933 Nov 30

Cytotoxic chemotherapy treatment for patients with advanced non-small-cell lung cancer (NSCLC) has reached a plateau, but further improvements are expected with integration of targeted therapies. Epidermal growth factor receptor (EGFR)-directed therapies are of particular interest because the EGFR is frequently expressed in tumors and associated with poorer outcome. Thus, blockade of the EGFR should improve outcome. Blockade can be achieved by tyrosine kinase inhibitors (TKIs) or monoclonal antibodies (MoAbs). Both approaches have been evaluated in advanced NSCLC. As single agents, EGFR-directed TKIs have demonstrated efficacy in patients previously treated with chemotherapy. When combined with first-line platinum-based chemotherapy, TKIs failed to improve the outcome. In contrast, MoAbs in combination with platinum-based first-line chemotherapy showed promising efficacy in phase II trials. Two phase III trials with chemotherapy with or without cetuximab have been performed in patients with advanced NSCLC. Other EGFR-directed MoAbs and TKIs are in earlier stages of clinical development.
Clin Lung Cancer 2008
PMID:Integrating epidermal growth factor receptor-targeted therapies into platinum-based chemotherapy regimens for newly diagnosed non-small-cell lung cancer. 1941 24

Fifteen percent of lung cancer cases occur in never-smokers and show characteristics that are molecularly and clinically distinct from those in smokers. Epidermal growth factor receptor (EGFR) gene mutations, which are correlated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), are more frequent in never-smoker lung cancers. In this study, microRNA (miRNA) expression profiling of 28 cases of never-smoker lung cancer identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., up-regulated miR-21) and unidentified (e.g., down-regulated miR-138) in those smoker cases. The changes in expression of some of these miRNAs, including miR-21, were more remarkable in cases with EGFR mutations than in those without these mutations. A significant correlation between phosphorylated-EGFR (p-EGFR) and miR-21 levels in lung carcinoma cell lines and the suppression of miR-21 by an EGFR-TKI, AG1478, suggest that the EGFR signaling is a pathway positively regulating miR-21 expression. In the never-smoker-derived lung adenocarcinoma cell line H3255 with mutant EGFR and high levels of p-EGFR and miR-21, antisense inhibition of miR-21 enhanced AG1478-induced apoptosis. In a never-smoker-derived adenocarcinoma cell line H441 with wild-type EGFR, the antisense miR-21 not only showed the additive effect with AG1478 but also induced apoptosis by itself. These results suggest that aberrantly increased expression of miR-21, which is enhanced further by the activated EGFR signaling pathway, plays a significant role in lung carcinogenesis in never-smokers, as well as in smokers, and is a potential therapeutic target in both EGFR-mutant and wild-type cases.
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PMID:MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. 1959 53

Epidermal growth factor receptor (EGFR) tyrosine kinase is commonly overexpressed in human cancers; however, the cellular mechanisms regulating EGFR expression remain unclear. p53, p63 and p73 are transcription factors regulating many cellular targets involved in controlling the cell cycle and apoptosis. p53 activates EGFR expression, whereas TAp63 represses EGFR transcription. The involvement of p73 in the regulation of EGFR has not been reported. Here, a strong correlation between EGFR overexpression and increased levels of the oncogenic DeltaNp73 isoform in head and neck squamous cell carcinoma (HNSCC) cell lines was observed. Ectopic expression of TAp73, particularly TAp73beta, resulted in suppression of the EGFR promoter, significant downregulation of EGFR protein and efficient induction of cell death in all six EGFR-overexpressing HNSCC cell lines. EGFR overexpression from a heterologous LTR promoter protected lung cancer cells from TAp73beta-induced EGFR suppression and apoptosis. Expression of TAp73beta efficiently induced promyelocytic leukaemia (PML) protein expression and PML knockdown by shRNA attenuated the downregulation of EGFR and induction of apoptosis by p73 in HNSCC cells. Furthermore, PML was found to be important for E1A-induced suppression of EGFR and subsequent killing of HNSCC cells. Our data therefore suggest a novel pathway involving PML and p73 in the regulation of EGFR expression.
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PMID:PML involvement in the p73-mediated E1A-induced suppression of EGFR and induction of apoptosis in head and neck cancers. 1959 75

Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.
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PMID:Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. 1968 Feb 94

Twenty-five percent of all lung cancer cases are not attributable to smoking. Epidermal growth factor receptor (EGFR) mutations, which are involved in approximately 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history. Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer. To investigate the chemopreventive effects of gefitinib on nonsmoking-related lung cancer, we generated transgenic mice expressing EGFR L858R in type II pneumocytes constitutively using the surfactant protein-C promoter. The transgenic mice invariably developed atypical adenomatous hyperplasia at age 4 weeks and multifocal adenocarcinoma of varying sizes at age 7 weeks. Notably, the expression levels of phosphorylated and total ErbB2, ErbB3, and thyroid transcription factor-1 were elevated in the transgenic mice compared with wild-type controls at age 3 weeks. Administration of gefitinib to 3-week-old transgenic mice for 1 week before carcinogenesis reduced the amount of phosphorylated EGFR in the lungs of the mice to the baseline level. Gefitinib (5 mg/kg/d; n = 5, 5, and 15) or vehicle (n = 5, 5, and 15) was administered to transgenic mice from age 3 to 8, 13, and 18 weeks, respectively. The numbers of lung tumors in the control and gefitinib-treated groups were 1.75, 5.8, 10.2, and 0 (P < 0.05), respectively. No fatal toxic events occurred in either group, and gefitinib inhibited tumorigenesis completely in this mouse model. These results suggest the utility of molecular targeted chemoprevention against nonsmoking-related lung cancer.
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PMID:Chemopreventive effects of gefitinib on nonsmoking-related lung tumorigenesis in activating epidermal growth factor receptor transgenic mice. 1969 Jan 48

Epidermal growth factor receptor (EGFR) overexpression in nonsmall cell lung carcinomas (NSCLC) is variable ranging from 19% to 89% and its prognostic value remains controversial. We tried to investigate (1) EGFR protein expression using four different antibodies, (2) the correlation between protein overexpression and EGFR gene amplification, and (3) the correlation between EGFR genetic status and clinicopathologic features in NSCLC. We examined EGFR protein expression using four different antibodies including Zymed EGFR kit (Clone 31G7), Dako EGFR pharmDx kit (Clone 2-18C9), Dako (Clone H11) and Novocastra (Clone EGFR 113) by immunohistochemical analysis. The protein overexpression was compared to gene amplification status by fluorescence in situ hybridization (FISH). EGFR protein overexpression was observed in 56% of tumors with Zymed EGFR kit, in 51% with Dako EGFR pharmDx kit, in 5% with Dako and in 18% with Novocastra (p=0.010). Both Zymed and Dako pharmDx kit were more sensitive than the Dako test (clone H11) and Novocastra clone EGFR 113. EGFR overexpression was more prominent in squamous cell carcinomas (SCC) than adenocarcinomas (ADC) (71% vs. 48%, p=0.001 with Zymed, 61% vs. 45%, p=0.011 with Dako pharmDx kit; respectively). EGFR FISH-positivity as represented by high polysomy and gene amplification was observed in 45% of the NSCLC patients. Protein expression levels significantly correlated with the gene copy number per tumor cell (p<0.001). Our data showed a higher percentage of positive cells detected by Zymed and Dako pharmDx tests. The EGFR protein overexpression rate varied from 4% to 72% according to different antibody clones and histologic types. EGFR protein expression detected by Zymed and Dako pharmDx was significantly associated with a high EGFR gene copy number.
Lung Cancer 2010 Jun
PMID:Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas: Comparison of four commercially available antibodies by immunohistochemistry and fluorescence in situ hybridization study. 1971 93

Targeting the epidermal growth factor receptor has played a central role in advanced non-small cell lung cancer research, treatment, and patient outcomes over the last several years; however, a number of questions about this approach remain to be addressed. Through the Istituto Toscano Tumori and the Italian Association of Women Against Lung Cancer Project, we collected 411 lung adenocarcinomas from several clinical centers in Tuscany. Mutations were assessed by sequencing exons 18-21 of the epidermal growth factor receptor gene, and by restriction fragment length polymorphism analysis of codons 12 and 13 of the K-RAS gene. Epidermal growth factor receptor mutations (12.6%) were more frequently observed in females (p<0.0001), in non-smokers (p=0.005), and in the presence of bronchioloalveolar features (p=0.0004). K-RAS mutations (17.9%) were more frequent in males (p=0.0007) and were associated with smoking habits (p=0.005). Epidermal growth factor receptor and K-RAS mutations were mutually exclusive (p=0.001). We focused on 21 female patients with advanced/metastatic lung adenocarcinoma who received gefitinib 250 mg/day (expanded access) or erlotinib 150 mg/die as second/third-line therapy; partial response was associated with classic epidermal growth factor receptor mutations (p=0.006) and with a non-smoking history (p=0.02). None of the female patients with partial response and/or stable disease showed K-RAS alterations. Although the data obtained in our study have yet to be analyzed and confirmed with a larger number of patients treated with tyrosine kinase inhibitors, they should provide useful information for targeted therapy, in particular for non-smoking female lung cancer patients.
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PMID:Epidermal growth factor receptor and K-RAS mutations in 411 lung adenocarcinoma: a population-based prospective study. 1972 44

Lung cancer is one of the most common cancers in the world. While historically, more men than women have died from lung cancer as a result of higher numbers of male smokers, the sex mortality ratio is now showing signs of narrowing. Tumors in women with lung cancer may be slightly different to those in men with lung cancer. This review focuses on biomarkers differentially expressed between female and male patients with lung cancer. There is variation in gene expression between men and women in some genes that encode carcinogen-metabolizing enzymes (CYP1A1, GSTM). Gastrin-releasing peptide (GRP), a bombesin-like peptide, is present in two actively transcribed alleles in women compared with men. Higher prevalence of infection with oncogenic variants human papilloma viruses (HPVs) HPV16 and HPV18 has been suggested in women. A higher frequency of G to T transversion was found in the p53 gene in lung tumors of women. KRAS mutation was found to be more frequent in women with resected non-small cell lung cancer (NSCLC) than in men with resected NSCLC. Epidermal growth factor receptor (EGFR) mutation is more frequently found in lung tumors from women, but the confounding effect of tobacco exposure may explain this difference. Lower levels of ERCC1 and BRCA1 have been reported in women with NSCLC. Lung tumors from women are more likely to express estrogen receptors than those from men. An in silico analysis of transcriptome datasets from lung cancer patients demonstrated that only seven genes (in at least two studies) had significantly different expression patterns in male versus female patients. All of these genes are localized on the sex chromosomes: one on chromosome X and six on chromosome Y. Many areas remain under debate and there are still significant gaps in our understanding, particularly how sex-linked factors relate to lung cancer risk, and to biological and clinical behaviors. Future research into lung cancer needs to address these gender differences more specifically.
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PMID:Differential expression of biomarkers in men and women. 1999 47


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