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)

Human carcinomas frequently express one or more members of the epidermal growth factor receptor family. Two family members, epidermal growth factor receptor (EGFR) and c-erbB2/neu (HER2), homodimerize or heterodimerize upon activation with ligand and trigger potent mechanisms of cellular proliferation, differentiation and migration. In this study, we examined the effect of the anti-EGFR monoclonal antibody Erbitux (cetuximab) on human tumor cells expressing both EGFR and HER2. Investigation of the effect of cetuximab on the activation of EGFR-EGFR, EGFR-HER2 and HER2-HER2 homodimers and heterodimers was conducted using the NCI-N87 human gastric carcinoma cell line. Treatment of NCI-N87 cells with cetuximab completely inhibited formation of EGFR-EGFR homodimers and EGFR-HER2 heterodimers. Activation of HER2-HER2 homodimers was not appreciably stimulated by exogenous ligand and was not inhibited by cetuximab treatment. Furthermore, cetuximab inhibited EGF-induced EGFR and HER2 phosphorylation in CAL27, NCI-H226 and NCI-N87 cells. The activation of downstream signaling molecules such as AKT, MAPK and STAT-3 were also inhibited by cetuximab in these cells. To examine the effect of cetuximab on the growth of tumors in vivo, athymic mice bearing established NCI-N87 or CAL27 xenografts were treated with cetuximab (1 mg, i.p., q3d). The growth of NCI-N87 and CAL27 tumors was significantly inhibited with cetuximab therapy compared to the control groups (p<0.0001 in both cases). In the CAL27 xenograft model, tumor growth inhibition by cetuximab treatment was similar to that by cetuximab and trastuzumab combination treatment. Immunohistological analysis of cetuximab-treated tumors showed a decrease in EGFR-HER2 signaling and reduced tumor cell proliferation. These results suggest that cetuximab may be useful in the treatment of carcinomas co-expressing EGFR and HER2.
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PMID:Anti-epidermal growth factor receptor monoclonal antibody cetuximab inhibits EGFR/HER-2 heterodimerization and activation. 1908 74

Receptor Tyrosine Kinases class I (RTK class I, EGF receptor family) constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. Activation of EGFR may be because of overexpression, mutations resulting in constitutive activation, or autocrine expression of ligand. In contrast, activation of HER2 occurs mainly by overexpression, which leads to spontaneous homodimerization and activation of downstream signaling events in a ligand-independent manner. EGFR and HER2 have now been validated as a clinically relevant target, and several different types of agents inhibiting these receptors are currently in development. The EGFR inhibitors Erlotinib, Gefitinib, and Cetuximab have undergone extensive clinical testing and have established clinical activity in non small cell lung cancer (NSCLS) and other types of solid tumors. Several of the other erbB inhibitors are also undergoing advanced clinical testing, either alone or in combination with other agents. This review reports various inhibitors, natural, small molecules and monoclonal antibodies, along with their reported activities for various members of erbB family. It will highlight the potential for the development of novel anti-cancer molecules.
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PMID:Receptor tyrosine kinase inhibitors as potent weapons in war against cancers. 1927 41

Cetuximab, which blocks ligand binding to epidermal growth factor receptor (EGFR), is currently being studied as a novel treatment for non-small cell lung cancer (NSCLC). However, its mechanisms of action toward metastasis, and markers of drug sensitivity, have not been fully elucidated. This study was conducted to (a) determine the effect of Cetuximab on invasion and NSCLC-metastasis; (b) investigate urokinase-type plasminogen activator receptor (u-PAR), a major molecule promoting invasion and metastasis, as a target molecule; (c) delineate molecular mediators of Cetuximab-induced metastasis inhibition; and (d) identify biomarkers of drug sensitivity in NSCLC. Cetuximab treatment resulted in reduced growth and Matrigel invasion of H1395 and A549 NSCLC cell lines, in parallel with reduced u-PAR mRNA and protein. u-PAR down-regulation was brought about by suppressing the binding of JunD and c-Jun to u-PAR promoter motif -190/-171 in vivo, and an inhibition of MAP/ERK kinase signaling. Furthermore, Cetuximab inhibited NSCLC proliferation and metastasis to distant organs in vivo as indicated by the chicken embryo metastasis assay. Low E-cadherin and high u-PAR, but not EGFR, was associated with resistance to Cetuximab in seven NSCLC cell lines. Furthermore, siRNA knockdown of u-PAR led to a resensitization to Cetuximab. Moreover, low E-cadherin and high u-PAR was found in 63% of resected tumor tissues of NSCLC patients progressing under Cetuximab therapy. This is the first study to show u-PAR as a target and marker of sensitivity to Cetuximab, and to delineate novel mechanisms leading to metastasis suppression of NSCLC by Cetuximab.
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PMID:Cetuximab attenuates metastasis and u-PAR expression in non-small cell lung cancer: u-PAR and E-cadherin are novel biomarkers of cetuximab sensitivity. 1927 67

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a major role in oncogenesis. Cetuximab is an EGFR-blocking antibody that is FDA approved for use in patients with metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC). Although cetuximab has shown strong clinical benefit for a subset of cancer patients, most become refractory to cetuximab therapy. We reported that cetuximab-resistant NSCLC line NCI-H226 cells have increased steady-state expression and activity of EGFR secondary to altered trafficking/degradation and this increase in EGFR expression and activity lead to hyper-activation of HER3 and down stream signals to survival. We now present data that Src family kinases (SFKs) are highly activated in cetuximab-resistant cells and enhance EGFR activation of HER3 and PI(3)K/Akt. Studies using the Src kinase inhibitor dasatinib decreased HER3 and PI(3)K/Akt activity. In addition, cetuximab-resistant cells were resensitized to cetuximab when treated with dasatinib. These results indicate that SFKs and EGFR cooperate in acquired resistance to cetuximab and suggest a rationale for clinical strategies that investigate combinatorial therapy directed at both the EGFR and SFKs in patients with acquired resistance to cetuximab.
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PMID:Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab. 1941 59

Cetuximab and panitumumab efficacy in metastatic colorectal cancer (mCRC) may be influenced by EGFR gene status and/or deregulation of its downstream signalling proteins detected in primary tumour. However, metastasis might have different molecular patterns with respect to primary tumour, possibly affecting the prediction of EGFR-targeted therapy efficacy. We analysed primary tumour and metastasis in 38 mCRC patients. Twelve cases were cetuximab/panitumumab treated. EGFR gene status and protein expression were investigated through fluorescent in situ hybridisation and immunohistochemistry (IHC), K-Ras/BRAF mutations by sequencing and PTEN expression by IHC. We observed EGFR gene deregulation in 25 out of 36 primary tumours and 29 out of 36 metastases, K-Ras mutations in 16 out of 37 cancers and in 15 out of 37 metastases, BRAF mutations in 2 out of 36 cancers and 2 out of 36 metastases and PTEN loss in 8 out of 38 cancers and 12 out of 38 metastases. For the first time in literature, we show that primary colorectal cancer and paired metastasis may exhibit difference with respect to EGFR pathway deregulation mechanisms possibly implying a different response to cetuximab or panitumumab treatment. The investigation of treated patients confirms this hypothesis. We therefore suggest that the analysis of metastatic lesion should be considered in patient management as well as in designing future clinical trials aimed to investigate the effect of anti-EGFR monoclonal antibodies in the treatment of mCRC.
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PMID:Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. 1958 70

Human epidermal growth factor (HER) family-targeted therapy combined with standard cytotoxic agents might improve the treatment of ovarian cancer. Human ovarian cancer cell lines OVCAR-3, IGROV-1, and SKOV-3 with differential EGFR, HER2, and HER3 expression levels were used to study whether EGFR-directed (cetuximab) or HER2-directed (trastuzumab, pertuzumab) monoclonal antibodies inhibited cell growth and abrogated activated receptor signaling routes. Possible increase of antiproliferative effects and further activation of caspase-3 as a read-out for apoptosis were analyzed when monoclonal antibodies were combined with docetaxel. Cetuximab alone inhibited cell growth in OVCAR-3 and IGROV-1, which was more pronounced when combined with pertuzumab in OVCAR-3. SKOV-3 cell growth was not significantly affected by any of the antibodies. Cetuximab increased the 50% growth-inhibiting effects of docetaxel in OVCAR-3 and IGROV-1, but not in SKOV-3. Coaddition of pertuzumab to cetuximab plus docetaxel in OVCAR-3 and IGROV-1, and, to a lesser extent trastuzumab in OVCAR-3, inhibited cell growth even further. Caspase-3 activation by docetaxel was enhanced after addition of cetuximab in OVCAR-3 and after addition of cetuximab plus pertuzumab in IGROV-1 and SKOV-3. Functional EGFR-signaling, HER2-signaling, and HER3-signaling routes as shown from abrogation of EGF-stimulated and heregulin-stimulated phosphorylated ERK1/2 by cetuximab, trastuzumab, and pertuzumab, respectively, were shown in OVCAR-3 and IGROV-1, but hardly in SKOV-3. Pertuzumab was able to abrogate phosphorylated HER2 by EGF and heregulin, except in SKOV-3. In conclusion, a combination of docetaxel with inhibitors of HER family members, such as cetuximab plus pertuzumab, may be considered for a clinical trial in ovarian carcinomas with functional receptors.
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PMID:Inhibition of functional HER family members increases the sensitivity to docetaxel in human ovarian cancer cell lines. 1936 59

Glucocorticoids such as dexamethasone are widely used as comedication in the treatment of head and neck cancer, e.g., to improve appetite and decrease weight loss and fatigue in patients with advanced disease or as antiallergic and antiemetic prophylaxis during anti-EGFR therapy. However, the literature suggests that dexamethasone induces resistance to antineoplastic agents in many solid tumor models in vitro and in vivo. Since this phenomenon has never been investigated in head and neck cancer, the present study was conducted to investigate the effect of dexamethasone on the antiproliferative activity of cetuximab in vitro in squamous cell carcinoma of the head and neck (SCCHN) cell lines. The antiproliferative effect of the anti-EGFR agent cetuximab alone and in combination with increasing concentrations of dexamethasone was examined in eight SCCHN cell lines at three different time-points (24, 48 and 72 h). Cell growth inhibition and viability were measured quantitatively using WST and LDH assays. Absolute tumor cell numbers were determined by cell counting in a Rosenthal chamber. Cetuximab alone inhibited the growth of all eight SCCHN cell lines significantly (p=0.008). In some cases the addition of dexamethasone reduced the antiproliferative activity of cetuximab (p<or=0.038) but remained significant in all of the eight SCCHN cell lines compared with untreated controls (p<or=0.028) at each drug concentration and each time-point. In contrast to the results reported for other tumor models, in our study dexamethasone showed in the majority of the evaluated dexamethasone drug concentrations and time-points no inhibition of the cytotoxic activity of cetuximab. The reasons for these discrepant findings are unclear but may be related to the degree of tumor cell differentiation or proliferation rate. Thus, further studies are required to elucidate the molecular mechanisms underlying the interaction between dexamethasone and cetuximab in different tumors.
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PMID:Does dexamethasone inhibit anticancer activity of cetuximab in squamous cell carcinoma cell lines of the head and neck? 1951 20

Cetuximab, an anti-EGFR human/mouse chimeric antibody, has just been approved in Japan for patients with EGFR positive unresectable or recurrent colorectal cancer, as monotherapy or in combination with irinotecan. We reported two cases of unresectable or recurrent colorectal cancer effectively treated by cetuximab after the progression of the prior chemotherapy. Case 1: A51-year-old male suffered from sigmoid colon cancer with synchronous liver metastases. He received cetuximab plus irinotecan combination therapy in the third-line setting. Amonth after the initiation of the chemotherapy, abdominal CT showed tumor shrinkage of liver metastases. Case 2: A57-year-old female suffered from sigmoid colon cancer with metachronous liver, ovarian metastases, ascites and pleural effusion. Her performance status(PS)according to ECOG performance scale was 1, and she complained of dyspnea on exertion. She received cetuximab monotherapy in the fourth-line setting. Five weeks after initiation of chemotherapy, her chest, abdominal and pelvic CT showed tumor shrinkage of the liver metastases and the reduction of both ascites and pleural effusion, together with resolution of her dyspnea on exertion. Before cetuximab administration, we investigated KRAS status on cancer tissue previously resected in the above 2 cases, which showed KRAS wild-type. Cetuximab could be effective for KRAS wild-type colorectal cancer, as well as the previous reports from Western countries.
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PMID:[Two cases of KRAS wild-type unresectable or recurrent colorectal cancer effectively treated by cetuximab after progression of prior chemotherapy]. 1954 25

Overexpression of the epidermal growth factor (EGF) receptor (EGFR) in cancer cells correlates with tumor malignancy and poor prognosis for cancer patients. For this reason, the EGFR has become one of the main targets of anticancer therapies. Structural data obtained in the last few years have revealed the molecular mechanism for ligand-induced EGFR dimerization and subsequent signal transduction, and also how this signal is blocked by either monoclonal antibodies or small molecules. Nimotuzumab (also known as h-R3) is a humanized antibody that targets the EGFR and has been successful in the clinics. In this work, we report the crystal structure of the Fab fragment of Nimotuzumab, revealing some unique structural features in the heavy variable domain. Furthermore, competition assays show that Nimotuzumab binds to domain III of the extracellular region of the EGFR, within an area that overlaps with both the surface patch recognized by Cetuximab (another anti-EGFR antibody) and the binding site for EGF. A computer model of the Nimotuzumab-EGFR complex, constructed by docking and molecular dynamics simulations and supported by mutagenesis studies, unveils a novel mechanism of action, with Nimotuzumab blocking EGF binding while still allowing the receptor to adopt its active conformation, hence warranting a basal level of signaling.
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PMID:Nimotuzumab, an antitumor antibody that targets the epidermal growth factor receptor, blocks ligand binding while permitting the active receptor conformation. 1958 89

The incidence of head and neck squamous cell carcinoma (HNSCC) has been gradually increasing over the last three decades. Recent data have now attributed a viral aetiology to a subset of head and neck cancers. Several studies indicate that oral human papillomavirus (HPV) infection is likely to be sexually acquired. The dominance of HPV 16 in HPV+ HNSCC is even greater than that seen in cervical carcinoma of total worldwide cases. Strong evidence suggests that HPV+ status is an important prognostic factor associated with a favourable outcome in head and neck cancers. Approximately 30 to 40% of HNSCC patients with present with early stage I/II disease. These patients are treated with curative intent using single modality treatments either radiation or surgery alone. A non-operative approach is favored for patients in which surgery followed by either radiation alone or radiochemotherapy may lead to severe functional impairment. Cetuximab, a humanized mouse anti-EGFR IgG1 monoclonal antibody, improved locoregional control and overall survival in combination with radiotherapy in locally advanced tumours but at the cost of some increased cardiac morbidity and mortality. Finally, the improved prognosis and treatment responses to chemotherapy and radiotherapy by HPV+ tumours may suggest that HPV status detection is required to better plan and individualize patient treatment regimes.
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PMID:HPV & head and neck cancer: a descriptive update. 1982 33


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