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

BRG1, also called SMARCA4, is the catalytic subunit of the SWI/SNF chromatin-remodelling complex and influences transcriptional regulation by disrupting histone-DNA contacts in an ATP-dependent manner. BRG1 and other members of the SWI/SNF complex become inactivated in tumours, implying a role in cancer development. To understand the contribution of BRG1 to lung tumourigenesis, we restored BRG1 in H1299 lung cancer cells and used cDNA microarray analysis to identify changes in gene expression. Forty-three transcripts became activated, whereas two were repressed. Chromatin immunoprecipitation of resulting candidate genes revealed that the CYP3A4 and ZNF185 promoters recruited BRG1 and that recruitment to the CYP3A4 promoter was specific to this gene and did not involve the CYP3A5 or CYP3A7 family members. Moreover, specifically BRG1 but not its homologue BRM was recruited to the CYP3A4 and ZNF185 promoters. To explore their potential relevance in lung tumours, levels of CYP3A4 and ZNF185 transcripts were evaluated in seven additional lung cancer cell lines. CYP3A4 was undetectable in any of the lung cancer cells tested, and only the CYP3A5 family member was present in the A549 and Calu-3 cells. In contrast, the amount of ZNF185 transcript clearly varied among lung cancer cell lines and severely reduced levels were observed in BRG1-deficient cells, except those of A427. We extended these observations to 27 lung primary tumours using real-time RT-PCR (TaqMan) and observed that four (15%) and 14 (52%) of them had BRG1 and ZNF185 downregulation, respectively, when compared with normal lung. No significant correlation between reduced levels of BRG1 and ZNF185 was observed, indicating that additional mechanisms to BRG1 inactivation may contribute to the loss of ZNF185 expression in lung tumours. In conclusion, our results provide evidence that transcriptional activation of ZNF185 and CYP3A4 is mediated by direct association of BRG1 with their promoters and also indicate that a decreased level of ZNF185 is a common feature of lung tumours and may be of biological relevance in lung carcinogenesis.
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PMID:Transcriptional targets of the chromatin-remodelling factor SMARCA4/BRG1 in lung cancer cells. 1573 Nov 17

Gefitinib (Iressa), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received < or = 2 (IDEAL1) or > or = 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were approximately 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.
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PMID:Gefitinib in non-small cell lung cancer. 1595 26

Gefitinib (Iressa) is a selective epidermal growth factor receptor tyrosine kinase inhibitor and is used for the treatment of lung cancer. Recently, we discovered that it inhibits the breast cancer resistance protein, which is an ATP-binding cassette transporter. P-glycoprotein (Pgp) also pumps multiple types of drugs out of the cell using energy generated from ATP, and confers multidrug resistance on cancer cells. This study was designed to examine whether gefitinib inhibits the function of Pgp. We used multidrug resistant PC-6/PTX lung cancer and MCF-7/Adr breast cancer cells which overexpress Pgp and measured their drug sensitivity and drug-efflux function by tetrazolium assay and flowcytometry, respectively. In addition, the drug-stimulated ATPase activity of Pgp was measured using insect membranes that express human Pgp. Epidermal growth factor receptor was expressed in MCF-7/Adr, but not in PC-6/PTX cells, and the overexpression of Pgp did not confer resistance to gefitinib to both cell types. However, clinically achievable levels of gefitinib moderately reversed the Pgp-mediated resistance to paclitaxel and docetaxel in Pgp overexpressing cells. In addition, gefitinib increased the intracellular accumulation of the Pgp substrate rhodamine-123 in resistant cells, and activated ATPase in a preparation of pure Pgp-expressing membrane. These findings suggest that gefitinib directly interacts with Pgp and inhibits its function. Gefitinib may clinically inhibit the excretion of Pgp substrate drugs including anticancer agents, and its drug-interaction should therefore be considered.
Lung Cancer 2005 Sep
PMID:Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. 1595 94

Mounting evidence exists that the activation of proto-oncogene by somatic mutation plays an important roles in the development of human cancers. Recent reports revealed that the kinase domain of ERBB2 gene, a proto-oncogene, is somatically mutated in the lung adenocarcinomas, suggesting the mutated ERBB2 gene may act as an oncogene in human cancers. The purpose of this was to see whether the ERBB2 kinase domain is mutated in other lung cancer types besides the adenocarcinoma. Here, we performed mutational analysis of the ERBB2 kinase domain by polymerase chain reaction-single strand conformation polymorphism assay in 114 non-adenocarcinoma type non-small cell lung cancers (NSCLCs) tissue samples, including 100 squamous cell carcinomas, three adenosquamous carcinomas and 11 large cell carcinomas. We detected the ERBB2 kinase domain mutation in one squamous cell carcinoma (1.0%). The detected ERBB2 mutation showed G to C transversion at bp 2305 (2305G>C), which would result in the substitution of Asp to His at codon 769 (D769H). The amino acid D769 is located in the alpha-helix within the kinase domain, which is important in the binding of ATP with ERBB2. We simultaneously analyzed the somatic mutations of EGFR, K-RAS, PIK3CA and BRAF genes in the squamous cell carcinoma with the ERBB2 mutation, and found that the tumor did not harbor any EGFR or ERBB2 or K-RAS or PIK3CA or BRAF gene mutation, either. This study demonstrated that in addition to lung adenocarcinoma ERBB2 kinase domain mutation could occur in lung squamous cell carcinomas, and suggested that alterations of ERBB2-mediated signaling pathway by ERBB2 mutations may occasionally contribute to the development of lung squamous cell carcinomas.
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PMID:ERBB2 kinase domain mutation in the lung squamous cell carcinoma. 1602 27

We describe a molecular resistance biomarker to gefitinib, epithelial membrane protein-1 (EMP-1). Gefitinib is a small-molecule inhibitor that competes for the ATP-binding site on EGF receptor (EGFR) and has been approved for patients with advanced lung cancers. Treatment with gefitinib has resulted in clinical benefit in patients, and, recently, heterozygous somatic mutations within the EGFR catalytic domain have been identified as a clinical correlate to objective response to gefitinib. However, clinical resistance to gefitinib limits the utility of this therapeutic to a fraction of patients, and objective clinical responses are rare. We aimed to assess the molecular phenotype and mechanism of in vivo gefitinib resistance in xenograft models and in patient samples. We generated in vivo gefitinib-resistance models in an adenocarcinoma xenograft model by serially passaging tumors in nude mice in presence of gefitinib until resistance was acquired. EMP-1 was identified as a surface biomarker whose expression correlated with acquisition of gefitinib resistance. EMP-1 expression was further correlated with lack of complete or partial response to gefitinib in lung cancer patient samples as well as clinical progression to secondary gefitinib resistance. EMP-1 expression and acquisition of gefitinib clinical resistance was independent of gefitinib-sensitizing EGFR somatic mutations. This report suggests the role of the adhesion molecule, EMP-1, as a biomarker of gefitinib clinical resistance, and further suggests a probable cross-talk between this molecule and the EGFR signaling pathway.
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PMID:Epithelial membrane protein-1 is a biomarker of gefitinib resistance. 1608 80

The protein-kinase family is the most frequently mutated gene family found in human cancer. Gefitinib, an ATP-competitive inhibitor of epidermal growth factor receptor (EGFR), also appears to be particularly effective in adenocarcinoma of the lung and in patients without smoking history. To determine whether lung tumors sensitive to gefitinib contained mutations within the tyrosine kinase (TK) domain of EGFR, we screened exons 18-23 of EGFR of tumors in 20 patients with non-small cell lung cancer (NSCLC) who had been treated with gefitinib. Nine (45%) tumors had TK domain mutations. All mutations were observed in adenocarcinoma. Seven (77.8%) of 9 cases with mutated types showed sensitivity to gefitinib, while no cases of 11 with wild type showed gefitinib sensitivity. Such mutations were more frequently observed in patients who had never smoked (5/8 or 62.5%) than in smokers (4/12 or 33.3%). The patients with mutations of EGFR to have a more favorable prognosis than those with wild type (p=0.033). These data show that adenocarcinomas from patients who had never smoked comprise a specific subset of patients with NSCLC sensitive to gefitinib treatment.
Lung Cancer 2006 Jan
PMID:Epidermal growth factor receptor mutations are associated with gefitinib sensitivity in non-small cell lung cancer in Japanese. 1619 42

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity to tyrosine kinase inhibitors (TKIs) and are present in 10-30% of non-small cell lung carcinoma depending on ethnic origin. EGFR protein is also overexpressed in about 90% of squamous cell carcinoma of head and neck (HNSCC), and treatment with TKIs has shown clinical benefit in a subgroup of these patients. Recently, EGFR mutations were described in three Asian patients with larynx cancer. We screened for EGFR tyrosine kinase mutations in tumour DNA of 100 patients of Caucasian origin with HNSCC by direct sequencing of the hotspot regions. Only one patient with larynx cancer displayed a novel, somatic EGFR missense mutation, K745R, affecting a highly conserved residue within the ATP cleft. Similar to reports in lung cancer, EGFR kinase domain mutations in HNSCC patients seem to show a lower incidence in patients of Caucasian origin.
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PMID:Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. 1632 36

Within the past 2 years, epidermal growth factor receptor (EGFR) inhibitors have moved from experimental agents to approved drugs for the management of advanced non-small cell lung cancer (NSCLC). This evolution has been accompanied by dramatic improvements in the understanding of how these drugs work and the clinical populations that may benefit. The identification of mutations in the ATP-binding domain of the EGFR that predict for dramatic responses introduces the possibility of truly individualized therapy in a subset of advanced NSCLC patients. The fact that these mutations may be more prevalent in certain patient populations, including patients of Asian ethnicity, female gender, and never-smoker status, raises intriguing questions regarding the pathogenesis of lung cancer. Another emerging area in the understanding of these agents revolves around the clinical observation that acneform rash may predict for superior outcome and the question of how this rash may relate to polymorphisms in the EGFR gene. EGFR polymorphisms, both germline and somatic, may be a relevant factor in unraveling the mechanism of the benefit of erlotinib in patients who do not harbor an EGFR ATP-binding site mutation. Numerous questions have arisen regarding how to best incorporate EGFR-targeted agents into patient management, as well as the role of the clinical laboratory in these decisions and the design of future trials.
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PMID:An update on the role of epidermal growth factor receptor inhibitors in non-small cell lung cancer. 1645 73

Despite advances in chemotherapeutics, overall survival for advanced lung cancer patients remains poor. Consequently, efforts have focused on the use of targeted therapies to improve response rates and survival. The epidermal growth factor receptor (EGFR) is overexpressed in a variety of cancers, including lung, and may play a critical role in the pathogenesis of disease. Small molecule tyrosine kinase inhibitors, such as gefitinib (Iressa(R)), have response rates of between 10 and 27% in Phase II trials, and anecdotal reports of dramatic and sustained responses. Two recent studies published simultaneously, identified mutations in the ATP-binding cleft of the EGFR that are associated with clinical response to gefitinib. This finding has extraordinary implications and serves as a critical step toward individualized, patient-specific treatment plans based on the molecular constitution of the tumor of each individual.
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PMID:Epidermal growth factor receptor mutations predict sensitivity to gefitinib in patients with non-small-cell lung cancer. 1655 22

A key feature of actin is its ability to bind and hydrolyze ATP. 8-Chloro-adenosine (8-Cl-Ado), which can be phosphorylated to the moiety of 8-Cl-ATP in living cells, inhibits tumor cell proliferation. Therefore we tested the hypothesis that 8-Cl-Ado can interfere with the dynamic state of actin polymerization. We found that 8-Cl-Ado inhibited the growth of human lung cancer cell line A549 and H1299 in culture, and arrested the target cells in G2/M phase evidenced by fluorescence-activated cell sorting (FACS). Immunocytochemistry showed that the normal organization of microfilaments was disrupted in 8-Cl-Ado-exposed cells, which is accompanied by the decrease of cell size and the alteration of cell shape, and by aberrant mitosis and apoptosis in targeted cells. Furthermore, in vitro light scattering assays revealed that 8-Cl-ATP could directly inhibit the transition of G-actin to F-actin. DNase I inhibition assays showed that the G/F-actin ratio, a surrogate marker of actin polymerization status in living cells, was significantly increased in 8-Cl-Ado-exposed A549 and H1299 cells, compared to the G/F-actin ratio in unexposed cells. Taken together, these results indicate that 8-Cl-Ado exposure can alter the dynamic properties of actin polymerization, disrupt the dynamic instability or the rearrangement ability of actin filaments. Therefore, our data suggest that 8-Cl-Ado may exert its cytotoxicity at least partly by interfering with the dynamic instability of microfilaments, which may correlate with its inhibitory effects on cell proliferation and cell death.
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PMID:8-Chloro-adenosine inhibits growth at least partly by interfering with actin polymerization in cultured human lung cancer cells. 1684 99


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