Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

For many decades, the use of chemotherapy as second-line therapy in non-small-cell lung cancer relied upon disease progression. Several studies have shown that four to six cycles of chemotherapy administered as front-line therapy treatment offers a survival advantage to patients; however, further chemotherapy beyond this initial treatment was more associated with side effects and no benefit in survival. Until 2009, second-line treatment for lung cancer was well established for three therapeutic agents: docetaxel, pemetrexed and erlotinib. Currently, the timeframe to use these agents has been challenged by two large randomized clinical trials in which pemetrexed (JMEN trial) and erlotinib (Sequential Tarceva in Unresectable NSCLC [SATURN] trial) were used as 'maintenance' therapy and shown to impact progression-free survival and overall survival. This review focuses on the actual dilemma that medical oncologists face in clinical practice in terms of when and to whom maintenance therapy should be applied or if the 'watch and wait' approach prior to start second-line therapy is still advisable.
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PMID:Accelerated second-line or maintenance chemotherapy versus treatment at disease progression in NSCLC. 2039 20

Approximately 213,380 new cases of non-small-cell lung cancer (NSCLC) were estimated to occur in the USA in 2007, which caused 160,390 NSCLC-related deaths. The majority of patients will be diagnosed with nonoperable, advanced-stage disease. Although combination chemotherapy remains the standard treatment, median survival with these regimens is only 8-10 months. Recent advances in our understanding of lung cancer on a molecular level have led to the introduction of targeted therapies. The EGF receptor (EGFR) was the first receptor to be proposed for cancer therapy and two EGFR-targeted pharmacologic approaches have been successfully developed: monoclonal antibodies (mAbs) and small-molecule inhibitors of the EGFR tyrosine kinase enzymatic activity. Erlotinib is a quinazoline derivative that selectively and reversibly inhibits the tyrosine kinase activity of the EGFR. Here, we review the mechanism(s) of action of erlotinib, as well as the results of Phase I, II and III trials with this drug in NSCLC, which have led to the worldwide approval of erlotinib treatment as monotherapy for therapy-refractory, advanced NSCLC patients.
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PMID:Erlotinib: an EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment. 2047 46

Non-small-cell lung cancer is a major subtype of lung cancer, which is the most common and fatal cancer in the world. Gefitinib (Iressa) and later erlotinib (Tarceva), specific tyrosine kinase inhibitors for EGF receptors (EGFRs), have been demonstrated to be effective for some non-small-cell lung cancer patients and used in clinics as pioneers of molecule-based targeted drugs for cancer. There has been an urgent need to develop biomarkers and to select appropriate patients who should benefit from treatment with these drugs because of the high sensitivity of target cancer cells. However, problems of acquired resistance after long-term treatment with these drugs have been recognized. Emerging evidence indicates that the efficacy of these drugs is partly dependent on somatic mutations in the EGFR. In this review, we summarize recent understandings of the molecular mechanisms that determine the efficacy of EGFR-tyrosine kinase inhibitors. Towards the end of this article, we discuss recent ongoing projects validating potential biomarkers and future prospects.
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PMID:Theme: oncology--molecular mechanisms determining the efficacy of EGF receptor-specific tyrosine kinase inhibitors help to identify biomarker candidates. 2047 7

Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR), such as erlotinib (Tarceva) and gefitinib (Iressa), have shown remarkable activity in a portion of patients with non-small-cell lung cancer (NSCLC). Based on a large randomized controlled trial showing a survival benefit compared with placebo, erlotinib gained US Food and Drug Administration approval for use in previously treated patients with NSCLC. However, its use in the first-line setting has been largely experimental. Recently, a large phase III randomized controlled trial demonstrated the superiority of first-line gefitinib therapy compared to combination chemotherapy in a clinically selected population consisting of Asian patients with adenocarcinoma and a light smoking history. This result was even more dramatic in the subset of patients whose tumors carried a mutation in the EGFR gene. Currently, randomized phase III trials of erlotinib as initial treatment of patients with EGFR mutant lung cancer are ongoing. In the setting of these recent developments, a review of the data regarding the use of erlotinib or gefitinib as initial therapy in the treatment of NSCLC is warranted. Currently active trials are referenced using their ClinicalTrials.gov identifier.
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PMID:Use of erlotinib or gefitinib as initial therapy in advanced NSCLC. 2048 Jul 37

Gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analog, and erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, are used clinically to treat patients with non-small-cell lung cancer (NSCLC). However, the molecular mechanisms for the drug resistance of gemcitabine in NSCLC cells are poorly understood. In this study, we used constructs containing human Rad51 cDNA or specific Rad51 small interfering RNA (siRNA) to examine the role of Rad51 in chemoresistance of gemcitabine in three different human NSCLC cell lines. Exposure of human NSCLC cell lines to gemcitabine increased the phosphorylation levels of mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 and AKT in a time- and dose-dependent manner, which was accompanied by an induction of Rad51 mRNA and protein expression. Gemcitabine increased the expression of Rad51 by increasing its mRNA and protein stability. Blockage of ERK1/2 or AKT activation by 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126; MKK1/2 inhibitor) or 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002; phosphatidyl inositol 3-kinase inhibitor), respectively, decreased the gemcitabine-induced Rad51 expression. Gemcitabine-induced cytotoxicity was significantly increased using siRNA depletion of Rad51 or blockage of ERK1/2 and AKT activation. Erlotinib enhanced the gemcitabine-induced cytotoxicity via the inactivation of ERK1/2 and AKT and the down-regulation of Rad51. Enforced expression of constitutively active MKK1/2 or AKT recovered cell viability and Rad51 protein levels that were decreased by the combination of erlotinib and gemcitabine. Suppression of Rad51 expression or the inactivation of ERK1/2 or AKT signaling may be considered potential therapeutic modalities for gemcitabine-resistant lung cancer.
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PMID:Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human non-small-cell lung cancer cells. 2085 43

Gefitinib (Iressa) and erlotinib (Tarceva), which target the epidermal growth factor receptor (EGFR), are approved for treatment of patients with advanced non-small cell lung cancer (NSCLC). Patients whose tumors harbor mutations in the EGFR gene, including delE746-A750 in exon 19 and L858R in exon 21, may benefit in particular from gefitinib treatment. However, acquired resistance to gefitinib has been a serious clinical problem, and further optimization is needed for application of EGFR-targeted drugs in lung cancer patients. In this study, we established gefitinib-resistant NSCLC cells from PC-9 cell line, which harbors the delE746-A750 mutation, by exposing the cell line to gefitinib for over 7 months. Gefitinib-resistant PC-9/GEFs cell lines showed a marked downregulation of PTEN expression and increased Akt phosphorylation. In revertant, gefitinib-sensitive clones (PC-9/Rev) derived from PC-9/GEF1-1 and PC-9/GEF2-1, PTEN expression, as well as sensitivity to gefitinib and erlotinib, was restored. Knockdown of PTEN expression using small interfering RNA specific for PTEN in PC-9 cells resulted in drug resistance to gefitinib and erlotinib. Nuclear translocation of the EGR1 transcription factor, which regulates PTEN expression, was shown to be suppressed in resistant clones and restored in their revertant clones. Reduced PTEN expression was also seen in tumor samples from a patient with gefitinib-refractory NSCLC. This study thus strongly suggests that loss of PTEN expression contributes to gefitinib and erlotinib resistance in NSCLC. Our findings reinforce the therapeutic importance of PTEN expression in the treatment of NSCLC with EGFR-targeted drugs.
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PMID:Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib-resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations. 2095 84

The purpose of this article is to provide updated recommendations for the diagnosis and treatment of patients non-small-cell lung cancer (NSCLC). The staging system for lung cancer has recently been revised by the International Association for Study of Lung Cancer and patients with NSCLC shall now be staged according to the UICC system 7th edition. Recommendations for treatment were based on treatment strategies that improve overall survival. In functionally fit patients with stage I-II disease surgical resection is recommended. Four cycles of adjuvant cisplatin-based chemotherapy is recommended in patients with pathologic stage II-III. For patients with stage IIIA and non-bulky mediastinal lymph node survival was significantly improved with induction chemotherapy plus surgical resection. Patients with unresectable or bulky stage IIIA and those with stage IIIB, should be treated with platinum-based chemotherapy and thoracic radiotherapy. For patients with metastatic disease and performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For elderly patients and those with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with platinum-based chemotherapy, except for patients with certain clinical characteristics. Maintenance therapy with pemetrexed or erlotinib increases survival in patients who did not progress after 4 cycles of a platinum based chemotherapy. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs.
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PMID:SEOM clinical guidelines for the treatment of non-small-cell lung cancer: an updated edition. 2097 65

The epidermal growth factor receptor (EGFR) plays an important role in cancer by activating downstream signals important in growth and survival. Inhibitors of EGFR are frequently selected as treatment for cancer including lung cancer. We performed an unbiased and comprehensive search for EGFR phosphorylation events related to somatic activating mutations and EGFR inhibitor (erlotinib) sensitivity. EGFR immunoprecipitation combined with high resolution liquid chromatography-mass spectrometry and label free quantitation characterized EGFR phosphorylation. Thirty (30) phosphorylation sites were identified including 12 tyrosine (pY), 12 serine (pS), and 6 threonine (pT). Site-specific phosphorylation was monitored by comparing ion signals from the corresponding unmodified peptide. Phosphorylation sites related to activating mutations in EGFR as well as sensitivity to erlotinib were identified using 31 lung cancer cell lines. We identified three sites (pY1092, pY1110, pY1172) correlated with activating mutations and three sites (pY1110, pY1172, pY1197) correlated with erlotinib sensitivity. Five sites (pT693, pY1092, pY1110, pY1172, and pY1197) were inhibited by erlotinib in concentration-dependent manner. Erlotinib sensitivity was confirmed using liquid chromatography coupled to multiple reaction monitoring (LC-MRM) and quantitative Western blotting. This LC-MS/MS strategy can quantitatively assess site-specific EGFR phosphorylation and can identify relationships between somatic mutations or drug sensitivity and protein phosphorylation.
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PMID:Mass spectrometry mapping of epidermal growth factor receptor phosphorylation related to oncogenic mutations and tyrosine kinase inhibitor sensitivity. 2108 Jun 93

The first-line treatment of advanced non-small-cell lung cancer (NSCLC) generally consists of a maximum of six cycles of platinum-based doublet chemotherapy followed by surveillance for disease progression. Recently, the strategy of starting second-line treatment immediately following the completion of chemotherapy, known as 'maintenance' chemotherapy, has been investigated. The use of maintenance pemetrexed improves both progression-free and overall survival, while the use of maintenance docetaxel did not significantly improve overall survival. The Sequential Tarceva in Unresectable NSCLC (SATURN) study investigated the use of maintenance erlotinib following the completion of first-line chemotherapy. It demonstrated a significant improvement in overall survival from 11.1 months in the placebo group to 12.3 months in patients receiving maintenance erlotinib, with the important caveat that only 21% of patients in the placebo group ever received erlotinib. A subset of patients whose tumors had EGF receptor mutations had a higher magnitude of benefit from maintenance treatment. Therefore, maintenance erlotinib should be considered in the treatment of patients with NSCLC.
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PMID:The SATURN trial: the value of maintenance erlotinib in patients with non-small-cell lung cancer. 2114 56

Chemotherapy is the standard of care for patients with advanced stage non-small cell lung cancer (NSCLC) because of the a modest improvement in survival and quality of life but its efficacy has already reached a plateau. Several molecular targets involved in the uncontrolled growth of lung cancer cells has been recently discovered and Epidermal Growth Factor Receptor (EGFR) pathway is as a key therapeutic target. Strategies to block such pathway include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. Erlotinib and gefitinib are two EGFR-TKI active against NSCLC. Their efficacy has been proven to be definitively superior in presence of activating EGFR mutation in the tumor. This evidence does not apply to the monoclonal antibody cetuximab, which efficacy in NSCLC was recently demonstrated in a single phase III study. The good tolerability profile of EGFR inhibitors make these agents suitable for maintenance and adjuvant setting, while sequencing of EGFR-TKIs and chemotherapy seems to be preferred. This article reviews the role of EGFR inhibitors focusing mainly on compounds in phase III clinical development.
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PMID:EGFR pathway in advanced non-small cell lung cancer. 2119 93


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