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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

K-RAS is currently the most promising biomarker in colorectal carcinoma (CRC). Functionally, the RAS protein plays a key role in the EGFR signaling pathway. In around 30-40% of all patients with CRC a mutated K-RAS gene can be found in the tumor, while 60-70% of patients express a wild-type K-RAS gene in the tumor. The K-RAS status is now generally regarded as a predictive factor for the response to anti-EGFR therapy: patients with the mutated K-RAS gene derive no benefit from treatment with the anti-EGFR antibodies cetuximab or panitumumab. The VEGF antibody bevacizumab, by contrast, seems to be efficacious with both wild-type K-RAS and mutated K-RAS - though larger-scale trials must still be carried out here.
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PMID:[Colorectal carcinoma--molecular markers in clinical routine]. 1903 96

Female rats of the BDII/Han inbred strain are prone to spontaneously develop endometrial carcinomas (EC) that in cell biology and pathogenesis are very similar to those of human. Human EC are classified into two major groups: Type I displays endometroid histology, is hormone-dependent, and characterized by frequent microsatellite instability and PTEN, K-RAS, and CTNNB1 (beta-Catenin) mutations; Type II shows non-endometrioid histology, is hormone-unrelated, displays recurrent TP53 mutation, CDKN2A (P16) inactivation, over-expression of ERBB2 (Her2/neu), and reduced CDH1 (Cadherin 1 or E-Cadherin) expression. However, many human EC have overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II. The EC developed in BDII rats can be related to type I tumors, since they are hormone-related and histologically from endometrioid type. Here, we combined gene sequencing (Pten, Ifr1, and Ctnnb1) and real-time gene expression analysis (Pten, Cdh1, P16, Erbb2, Ctnnb1, Tp53, and Irf1) to further characterize molecular alterations in this tumor model with respect to different subtypes of EC in humans. No mutation in Pten and Ctnnb1 was detected, whereas three tumors displayed sequence aberrations of the Irf1 gene. Significant down regulation of Pten, Cdh1, p16, Erbb2, and Ctnnb1 gene products was found in the tumors. In conclusion, our data suggest that molecular features of spontaneous EC in BDII rats can be related to higher-grade human type I tumors and thus, this model represents an excellent experimental tool for research on this malignancy in human.
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PMID:Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats. 1907 38

Targeted therapy has vastly improved outcomes in certain types of cancer. Extension of this paradigm across a broad spectrum of malignancies will require an efficient method to determine the molecular vulnerabilities of cancerous cells. Improvements in sequencing technology will soon enable high-throughput sequencing of entire genomes of cancer patients; however, determining the relevance of identified sequence variants will require complementary functional analyses. Here, we report an RNAi-assisted protein target identification (RAPID) technology that individually assesses targeting of each member of the tyrosine kinase gene family. We demonstrate that RAPID screening of primary leukemia cells from 30 patients identifies targets that are critical to survival of the malignant cells from 10 of these individuals. We identify known, activating mutations in JAK2 and K-RAS, as well as patient-specific sensitivity to down-regulation of FLT1, CSF1R, PDGFR, ROR1, EPHA4/5, JAK1/3, LMTK3, LYN, FYN, PTK2B, and N-RAS. We also describe a previously undescribed, somatic, activating mutation in the thrombopoietin receptor that is sensitive to down-stream pharmacologic inhibition. Hence, the RAPID technique can quickly identify molecular vulnerabilities in malignant cells. Combination of this technique with whole-genome sequencing will represent an ideal tool for oncogenic target identification such that specific therapies can be matched with individual patients.
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PMID:RNAi screen for rapid therapeutic target identification in leukemia patients. 1943 5

More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-alpha (TNFalpha)-induced apoptosis. When the dynamics of phosphorylated ERK response to TNFalpha were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-alpha. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-alpha autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNFalpha treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence.
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PMID:RAS mutations affect tumor necrosis factor-induced apoptosis in colon carcinoma cells via ERK-modulatory negative and positive feedback circuits along with non-ERK pathway effects. 1978 36

Malignant mesothelioma (MM) is a tumor with poor prognosis associated with asbestos exposure. While it remains to be clarified how asbestos fibers confer genetic/epigenetic alterations and induce cellular transformation in normal mesothelial cells, the understanding of key molecular mechanisms of MM cell development, proliferation, and invasion has progressed. MM shows frequent genetic inactivation of tumor suppressor genes of p16(INK4a)/p14(ARF) and neurofibromatosis type 2 (NF2) which encodes Merlin, and epigenetic inactivation of RASSF1A. However, no frequent mutations of well-known oncogenes such as K-RAS and PIK3CA have been identified. Activation of multiple receptor tyrosine kinases including the epidermal growth factor receptor (EGFR) family and MET, and subsequent deregulations of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)-AKT signaling cascades are frequently observed in most MM cells. The tumor suppressive function of Merlin in MM cells is also being investigated by dissecting its possible downstream signaling cascade called the Hippo pathway. Further comprehensive delineation of dysregulated signaling cascades in MM cells will lead to identification of key addiction pathways for cell survival and proliferation of MM cells, which strongly promote establishment of a new molecular target therapy for MM.
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PMID:Genomic abnormalities and signal transduction dysregulation in malignant mesothelioma cells. 1979 48

This study aimed to describe a short-term ex vivo assay to predict response to epidermal growth factor receptor (EGFR) targeted therapy (gefitinib) in adenocarcinoma patients. Four patients with locally advanced esophageal adenocarcinoma were treated with gefitinib (250 mg/day) for 14 days and pharmacokinetic (PK) studies were conducted to monitor plasma drug concentrations. Tumor cells were sampled by endoscopic biopsy prior to (baseline, day 0) and at the completion of (day 14) treatment. Cells obtained at baseline were exposed to gefitinib in short-term cell culture conditions (ex vivo assay). Western blot analyses with phospho-specific antibodies were performed to evaluate activation and biochemical response to therapy of EGFR and its downstream signaling components ERK and AKT ex vivo and in vivo. The in vivo profiles were correlated with the gefitinib-mediated alteration in proliferating cell nuclear antigen (PCNA) expression, a marker of cell proliferation. The correlation between EGFR expression and ERK activity was also investigated by immunohistochemical analysis in pretreatment biopsies. Mutational status of the genes encoding EGFR, K-RAS, and PI3KCA (the phosphoinositide 3-kinase catalytic subunit p110) as well as expression levels of PTEN protein were tested in order to investigate potential confounders of the gefitinib effect. All patients completed the gefitinib therapy. PK studies demonstrated constant gefitinib concentrations during the treatment, confirming persistent exposure of target tissue to the drug at sufficient levels to achieve EGFR blockade. Ex vivo culture with gefitinib resulted in distinct response patterns representing various states of activity of the ERK and AKT pathways. The results of the ex vivo studies correctly predicted the pharmacodynamic (PD) effects of the agents in tumor tissue in vivo. PCNA expression correlated with ERK pathway inhibition, but not with gefitinib-mediated inhibition of EGFR activity alone. Immunohistochemical analysis performed on pretreatment biopsies correlated with Western blot analysis of EGFR and phospho-ERK expression. No mutations were identified in exons 18-21 of EGFR, exons 2 and 3 of K-RAS or exons 9 and 22 of PI3KCA. Levels of PTEN were comparable across tumors. The novel pharmacodynamic approach described in this proof of principle study may be useful to refine the patient selection to maximize the potential benefits of drugs and design individualized rational therapies for cancer patients.
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PMID:A novel pharmacodynamic approach to assess and predict tumor response to the epidermal growth factor receptor inhibitor gefitinib in patients with esophageal cancer. 1995 29

Seventy to 40% of K-RAS wild type colorectal tumors does not seem to benefit from treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies. Recent data suggested that in presence of IGF-1 system, altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. The interaction between IGF-1 expression and K-RAS mutational analysis was tested to verify the ability of IGF-1 to identify a subgroup of patients more likely to benefit from EGFR-targeted antibodies treatment. IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. One hundred twelve patients were analyzed. IGF-1 was negative in 30 patients (27%) and overexpressed in the remaining 82 cases (73%). In IGF-1 negative and IGF-1 positive tumors, we observed progressive disease in 9 (30%) and 55 (67%) patients, respectively (p = 0.001). Median progression-free survival was 7.5 mo in patients showing IGF-1 negative tumors and 3 mo for IGF-1 expressing tumors (p = 0.002). Among K-RAS wild type patients, IGF-1 negative and positive tumors showed a partial response to cetuximab-irinotecan in 13 (65%) and 11 (22%) cases, respectively (p = 0.002). Median progression-free survival in IGF-1 negative tumors was 10 mo and 3.2 mo in IGF-1 positive colorectal cancers (p = 0.02). IGF-1 proved to be a possible predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer. Combined IGF-1 and K-RAS analysis may represent an effective strategy for a better selection of responding colorectal cancer patients.
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PMID:Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan. 2009 80

KRAS mutations are proved as a predictor of response to EGFR-targeted therapies for patients with metastatic colorectal cancer. For identifying the wild-type KRAS (wt-KRAS) responder subset of patients who will benefit from novel agents our laboratory has introduced the TheraSreen K-RAS Mutation Kit(R) an allele-specific RT-PCR based assay. Our aim is to describe the validation procedure of this method in our laboratory, determine the portion of colorectal cancer patients with wt-KRAS status, and assess the prognostic power of mutational status for the anti-EGFR therapy outcome in colorectal cancer patients. In this study 302 samples from 273 patients with metastatic colorectal cancer were tested for 7 most common mutations on codon 12 and 13 of the KRAS gene. We used HT-29 and CCL-247 cell lines to determine the sensitivity of the method for different proportions of tumor cells in the sample. We determined that 2% of cells carrying a KRAS mutation must be present in the sample for an undisputable detection of mutated signal using the LightCycler Adapt Software. Among the tested patients 54.5% had a wt-KRAS genotype and 45.5% had a mutated KRAS genotype. The p.Gly12Asp was the most common detected mutation (38.5%). Among the cetuximab therapy responders, 85.7% had a wt-KRAS genotype. We have shown that the RT-PCR method introduced to discriminate between anti-EGFR therapy responders and non-responders is efficient, reliable and quickly applicable. The ratio of mutated versus wt-KRAS patients in our study is similar to ratios reported by other authors, as is the high correlation between wt-KRAS genotype and response to cetuximab therapy. Nevertheless the selection of patients for treatment solely on the basis of KRAS status is not perfect due to the fact that some responders are among the patients with mutated KRAS and some non-responders among the wt-KRAS patients.
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PMID:KRAS mutations in Slovene patients with colorectal cancer: frequency, distribution and correlation with the response to treatment. 2037 87

Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal-regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1-inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1alpha (HIF-1alpha)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1alpha and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1alpha expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression.
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PMID:Early growth response-1 induces and enhances vascular endothelial growth factor-A expression in lung cancer cells. 2048 56

Medical treatment of metastatic colorectal carcinoma has become more effective in recent years. In addition to an increasing number of cytotoxic drugs (e.g. fluoropyrimidines, irinotecan, oxaliplatin), monoclonal antibodies against VEGF or the EGF receptor have become available. These developments, combined with an increasing number of metastasectomies, have improved the prognosis of patients with metastatic colorectal cancer to a median survival of 24-30 months.Starting with the determination of K-RAS mutations the first molecular markers have found a place in the routine diagnostics i. e. to predict which patients have a higher chance (K-RAS wild type) or very low chance (K-RAS mutation) to respond to EGFR antibody treatment. This information complements important clinical factors for the choice of the therapeutic regimen, such as the treatment target (e.g. neoadjuvant treatment of non-resectable liver metastases), tumor symptoms which urgently require a tumor response and comorbidities.
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PMID:[Current medicinal treatment of metastasized colorectal carcinoma]. 2057 92


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