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)

The incidence of several extracolonic tumors, such as duodenal carcinoma, is higher in familial adenomatous polyposis (FAP) patients than in the general population, but there is little information about lung carcinoma in FAP. A 43-year-old woman presented with a lung tumor 17 years after total colectomy for FAP. Pathohistological analysis of the lung tumor demonstrated mixed adenocarcinoma consisting of a papillary adenocarcinoma component and a bronchioloalveolar carcinoma component. Sequencing analysis indicated a germline APC mutation from TCA to TGA (stop) at codon 1110, but no pathogenic germline MYH mutations. The other APC allele in the lung carcinoma was not inactivated by somatic mutations, promoter methylation, or chromosomal deletion. No somatic mutations in any of the coding regions of the p53 gene or in the mutation hot spot regions of the K-ras or EGFR genes were detected in the carcinoma. Amplification, however, of three chromosome regions, 5p, 8q, and 12q14-12q21, was identified in the carcinoma on genome-wide high-resolution single-nucleotide polymorphism (SNP) microarray. The present results suggest that the chromosomal copy number alterations detected on SNP microarray were involved in the carcinogenesis of the adenocarcinoma of the lung in the present FAP patient.
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PMID:Characterization of adenocarcinoma of the lung in a familial adenomatous polyposis patient. 1884 36

The mutated K-ras gene is involved in approximately 30% of human cancers. In order to search for K-ras oncogene-induced modulators in lung tissues of K-ras transgenic mice, we performed microarray and proteomics (LC/ESI-MS/MS) analysis. Genes (RAB27b RAS family, IL-1RA, IL-33, chemokine ligand 6, epiregulin, EGF-like domain and cathepsin) related to cancer development (Wnt signaling pathway) and inflammation (chemokine/cytokine signaling pathway, Toll receptor signaling) were up-regulated while genes (troponin, tropomodulin 2, endothelial lipase, FGFR4, integrin alpha8 and adenylate cyclase 8) related to the tumor suppression such as p53 pathway, TGF-beta signaling pathway and cadherin signaling pathway were down-regulated by K-ras oncogene. Proteomics approach revealed that up-regulated proteins in lung adenomas of K-ras mice were classified as follows: proteins related to the metabolism/catabolism (increased from 7 to 22% by K-ras gene), proteins related to translation/transcription and nucleotide (from 4 to 6%), proteins related to signal transduction (from 3 to 5%), proteins related to phosphorylation (from 1 to 2%). ATP synthase, Ras oncogene family, cytochrome c oxidase, flavoprotein, TEF 1, adipoprotein A-1 BP, glutathione oxidase, fatty acid BP 4, diaphorase 1, MAPK4 and transgelin were up-regulated by K-ras oncogene. However, integrin alpha1, Ras-interacting protein (Rain), endothelin-converting enzyme-1d and splicing factor 3b were down-regulated. These studies suggest that genes related to cancer development and inflammation were up-regulated while genes related to the tumor suppression were down-regulated by K-ras, resulting in the tumor growth. Putative biomarkers such as cell cycle related genes (Cdc37), cancer cell adhesion (Glycam 1, integrin alpha8, integrin alphaX and Clec4n), signal transduction (Tlr2, IL-33, and Ccbp2), migration (Ccr1, Ccl6, and diaphorase 1 (Cyb5r3) and cancer development (epiregulin) can be useful for diagnosis and as prognosis markers and some of the target molecules can be applied for prevention of cancer.
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PMID:Profiling of transcripts and proteins modulated by K-ras oncogene in the lung tissues of K-ras transgenic mice by omics approaches. 1908 87

In an effort to improve the survival of cancer patients, new therapeutic approaches focusing on the molecular mechanisms that mediate tumour cell growth or survival have gained much attention. In particular, EGF-R and VEGF/VEGF-R have been extensively investigated as targets for anti-neoplastic therapy. Agents that selectively target EGF-R, erbB-2, VEGF-R-2 or VEGF have shown promising activity in clinical trials, and several are now approved for use in selected cancer indications. However, all patients ultimately develop resistance to these drugs. Thus, there is a great need to understand how patients become resistant to effective therapies for these cancers since this approach may lead to improvements in therapies that target EGF-R and VEGF/VEGF-R. Pre-clinical studies have begun to shed light on the mechanisms of resistance to anti-angiogenetic drugs and to date four mechanisms of resistance have been identified (1) upregulation of bFGF, (2) overexpression of MMP-9, (3) increased levels of SDF-1alpha and (4) HIF-1alpha-induced recruitment of bone marrow-derived CD45+ myeloid cells. In addition, the molecular mechanisms of resistance to EGF-R modulating agents can be attributed to several general processes: (1) activation of alternative tyrosine kinase inhibitors that bypass the EGF-R pathway (e.g. c-MET and IGF-1R), (2) increased angiogenesis, (3) constitutive activation of downstream mediators (e.g. PTEN and K-ras) and (4) the existence of specific EGF-R mutations. K-ras mutations have been significantly associated with a lack of response to EGF-R tyrosine kinase inhibitors in patients with NSCLC and with a lack of response to cetuximab or to panitumumab in patients with advanced colorectal cancer. The identification of these resistance mechanisms has led to clinical trials using newly designed targeted therapies that can overcome resistance and have shown promise in laboratory studies. Ongoing research efforts will likely continue to identify additional resistance mechanisms, and these findings will hopefully translate into effective therapies for different cancers.
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PMID:Resistance to EGF-R (erbB-1) and VEGF-R modulating agents. 1912 37

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m(-2) at week 1 and 250 mg m(-2) weekly thereafter until disease progression. Oxaliplatin (100 mg m(-2)) and leucovorin (100 mg m(-2)) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m(-2)) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1-65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5-6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-alpha levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.
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PMID:Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. 1912 59

Recent molecular studies support the hypothesis that clear cell carcinoma and mucinous adenocarcinoma are refractory cancers that are biologically distinct from serous adenocarcinoma. Treatment of these cancers has not yet been adequately tested, so separate clinical trials are needed for each type. Paclitaxel(175 mg/m2/3hr)combined with carboplatin AUC 6(TC regimen)is the current gold standard for treating ovarian cancer. Clear cell carcinoma and mucinous adenocarcinoma are less sensitive to a TC regimen than serous adenocarcinoma, and an international randomized trial for clear cell carcinoma is now underway(GCIG/JGOG3017). Targeted therapy is attractive for chemoresistant clear cell carcinoma, thus VEGFR inhibitor(sunitinib), PDGFR inhibitor(sorafenib), m-TOR inhibitor (temsirolimus), and monoclonal antibody(bevacizumab)are being evaluated. Mucinous adenocarcinoma often shows CK20- and CEA-positive patterns in immunohistochemistry, and furthermore, p53-negative and K-ras-positive in molecular markers, which suggests that mucinous adenocarcinoma resembles colorectal, stomach, and pancreas cancers more than serous ovarian adenocarcinoma. Trials are needed to test the agents effective for gastrointestinal cancer. The GOG will start a randomized phase III trial comparing TC regimen with capecitabine plus oxaliplatin(GOG241). We are starting a phase II study of S-1 plus oxaliplatin in Japan. For refractory cancers, molecular biology-based, cross- organ treatment with cytotoxic/cytostatic agents is needed.
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PMID:[Treatments of epithelial ovarian cancer by histologic subtype]. 1922 34

Noonan syndrome (NS OMIM 163950) is a relatively common autosomal dominant developmental disorder characterized by short stature, specific facial features, and congenital cardiac anomalies. Approximately 50-66% of cases have defined mutations in the K-ras/Raf/MEK/ERK pathway that lead to constitutive signaling, but a significant number remain unexplained. We hypothesize that enhanced signaling through Galpha(i2) (from the GNAI2 gene) may also produce a NS-like phenotype. This is based on a recently described mouse model in which RGS-mediated inhibition of Galpha(i2) is prevented by a knock-in mutation (G184S) that blocks RGS binding [Huang et al., Mol. Cell. Biol. 2006;26:6870-9]. The mice have short body length, cardiac hypertrophy, a triangular face with wide-set eyes and ears, and hematologic alterations. There is a slight increase in ERK activation and a pronounced enhancement of PI3K/Akt phosphorylation in MEFs from these mice suggesting that abnormal increases in Galpha(i2) signaling could represent a novel upstream mechanism for NS. This suggests a novel set of candidate genes for NS (GNAI2 and RGS proteins) and if validated could have important implications for therapy as well.
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PMID:GNAI2 and regulators of G protein signaling as a potential Noonan syndrome mechanism. 1928 10

Sorafenib is a multikinase inhibitor that has shown promising therapeutic results in different tumor histotypes, both as a single agent or in combination with other treatments. We analyzed the in vitro activity of sorafenib in pancreatic cancer, one of the most lethal and chemo-radio-resistant tumors, using four human pancreatic cancer cell lines (t3m4, Capan 1, Capan 2, and MiaPaca 2), characterized by different K-ras gene status and RAF/MEK/ERK profile. Sorafenib exerted a strong anti-proliferative effect independently of RAS/RAF/MEK/ERK and induced various degrees of apoptosis in the cell lines. The mechanisms involved were explored in detail in t3m4 and Capan 1, in which sorafenib induced the highest and lowest levels of apoptosis, respectively. In t3m4, the RAF/AKT/STAT-3 rather than the RAF/MEK/ERK pathway was involved, whereas in Capan 1 cells there was a strong decrease in pMEK and pERK which was not accompanied by an important reduction in RAF, AKT, and STAT-3 proteins or in their phosphorylation. Moreover, U0126-induced MEK inhibition did not induce apoptosis in any cell line, reinforcing the hypothesis of a MEK/ERK-independent mechanism of sorafenib activity. Mcl-1 appears to play a crucial role in sorafenib-induced apoptosis. In fact, both protein and mRNA were downregulated in t3m4 and upregulated in Capan 1, in which siRNA-induced silencing resulted in the same level of apoptosis as observed in t3m4. Our results show that sorafenib exerts anti-proliferative and pro-apoptotic activity in pancreatic cancer cells. Used singly or in combination with other drugs, it could therefore represent valid treatment for pancreatic cancer.
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PMID:Role of RAF/MEK/ERK pathway, p-STAT-3 and Mcl-1 in sorafenib activity in human pancreatic cancer cell lines. 1928 93

Neoadjuvant chemoradiotherapy is considered at the present time as the standard treatment of most T3-4 rectal cancer. In France a combination of radiotherapy (45 Gy/5 weeks) with concurrent capecitabine (1,600 mg/m2) is the most popular protocol. Randomized trials try to optimize this approach using new cytotoxic drugs and/or radiation dose-escalation. The introduction of biotargeted therapies (anti-EGFR or antiangiogenic) is an attractive field especially selecting the treatment according to K-ras mutation. For T2 and 'early T3' present studies are using neoadjuvant chemoradiation followed by transanal local excision in case of good tumor response. In frail elderly patients, a new trend is to use mainly exclusive irradiation to control the tumor and avoid the excessive toxicity of open surgery in this group of patients. As rectal cancer is presenting many different clinical situations, an individualised treatment appears justified.
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PMID:[Neoadjuvant approach for non-metastatic rectal cancer combining radiotherapy and chemotherapy. Biotargeted drugs]. 1931 10

Micropapillary lung adenocarcinoma (MPA) has been reported as an aggressive variant of adenocarcinoma, frequently manifesting at high stage with a poor prognosis. We analyzed the clinical and molecular profile of 15 primary MPAs for K-ras, EGFR, and BRAF mutations and performed fluorescence in situ hybridization for EGFR amplification. In our study, 11 (73%) of 15 MPAs harbored mutually exclusive mutations: 5 (33%) K-ras, 3 (20%) EGFR, and 3 (20%) BRAF. Mutations in all 3 genes occurred in patients with a smoking history and tumors with mucinous differentiation and secondary lepidic, acinar, and solid growth, suggesting that in a Western population, cytomorphologic correlation with genetic mutations is more unpredictable than in Japanese cohorts. We conclude that K-ras, EGFR, and BRAF mutations are disproportionately seen in adenocarcinomas of lung with a dominant micropapillary growth pattern compared with conventional adenocarcinoma in our institutional experience.
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PMID:Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. 1936 18

A subset of neoplastic cells within human high-grade gliomas has features associated with stem cells. These cells may sustain glioma growth, and their stem-like properties may confer resistance to standard glioma treatments. Whether glioma stem cells derive from indigenous neural stem cells (NSC), or from tumor cells that have reacquired stem cell-like properties, is unknown. However, signaling pathways that are tightly regulated and central to NSC biology, including the Ras/Raf/Erk pathway, are hyperactive and pathogenic in gliomagenesis. Furthermore, data in animal models suggests that, in some cases, tumors are initiated in the subventricular zone (SVZ), a stem/progenitor cell niche in the mature brain. We activated oncogenic K-ras in mouse glioneuronal precursor cells and adult SVZ cells using GFAP-Cre. GFAP-Cre+/K-ras(G12D) mice showed a marked expansion of glial fibriallary acidic protein (GFAP)- and TUJ1-expressing cell populations in the SVZ. In addition, mice developed intermediate grade, infiltrating glioma with 100% penetrance. Tumors were consistently located in the amygdalohippocampal region and nearby cortex, often in association with the lateral ventricle and expanded SVZ. Tumor cells expressed markers associated with neural progenitor cells, including Olig2, Bmi-1, and PDGFR-alpha. These data suggest that infiltrating tumor cells may arise from NSC transformed by activation of oncogenic K-ras in vivo.
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PMID:GFAP-Cre-mediated activation of oncogenic K-ras results in expansion of the subventricular zone and infiltrating glioma. 1943 21


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