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)

Epidermal growth factor receptor (EGFR) is a member of the ERBB family of receptor tyrosine kinases that has been shown to play an important developmental and physiologic role in many aspects of pregnancy. We have previously shown in mice that Egfr(tm1Mag) nullizygous placentas have fewer proliferative trophoblasts than wild-type and exhibit strain-specific defects in the spongiotrophoblast and labyrinth layers. In this study we used mice with the hypermorphic Egfr(Dsk5) allele to study the effects of increased levels of EGFR signaling on placental development. On three genetic backgrounds, heterozygosity for Egfr(Dsk5) resulted in larger placental size with a more prominent spongiotrophoblast layer and increased expression of glycogen cell-specific genes. The C3HeB/FeJ strain showed additional placental enlargement of Egfr(Dsk5) homozygotes with a significant number of homozygous embryos dying prior to 15.5 days post-coitus (dpc). We also observed strain-specific subfertility in Egfr(Dsk5) heterozygous females and pregnancy loss was dependent on maternal factors rather than embryo genotype. Higher levels of phospho-EGFR were detected in the uterus of Egfr(Dsk5) heterozygotes but the structure of Egfr(Dsk5) heterozygous nonpregnant uteri appeared similar to wild-type. Collectively, our results demonstrate that mice with increased levels of EGFR signaling exhibit an extensive level of genetic background-dependent phenotypic variability. In addition, EGFR promotes growth of the placental spongiotrophoblast layer in mice, and EGFR expressed in the uterine stroma may play an underappreciated role in preparation of the uterus for embryo implantation.
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PMID:Placental overgrowth and fertility defects in mice with a hypermorphic allele of epidermal growth factor receptor. 1946 82

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) inhibit the function of certain adenosine triphosphate (ATP)-binding cassette transporters, including P-glycoprotein/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2. We previously reported an antagonistic activity of gefitinib towards BCRP. We have now analyzed the effects of erlotinib, another EGFR-TKI, on P-glycoprotein and BCRP. As with gefitinib, erlotinib effectively reversed BCRP-mediated resistance to SN-38 (7-ethyl-10-hydroxycamptothecin) and mitoxantrone. In contrast, we found that erlotinib effectively suppressed P-glycoprotein-mediated resistance to vincristine and paclitaxel, but did not suppress resistance to mitoxantrone and doxorubicin. Conversely, erlotinib appeared to enhance P-glycoprotein-mediated resistance to mitoxantrone in K562/MDR cells. This bidirectional activity of erlotinib was not observed with verapamil, a typical P-glycoprotein inhibitor. Flow cytometric analysis showed that erlotinib co-treatment restored intracellular accumulation of mitoxantrone in K562 cells expressing BCRP, but not in cells expressing P-glycoprotein. Consistently, erlotinib did not inhibit mitoxantrone efflux in K562/MDR cells although it did vincristine efflux in K562/MDR cells and mitoxantrone efflux in K562/BCRP cells. Intravesicular transport assay showed that erlotinib inhibited both P-glycoprotein-mediated vincristine transport and BCRP-mediated estrone 3-sulfate transport. Intriguingly, Lineweaver-Burk plot suggested that the inhibitory mode of erlotinib was a mixed type for P-glycoprotein-mediated vincristine transport whereas it was a competitive type for BCRP-mediated estrone 3-sulfate transport. Collectively, these observations indicate that the pharmacological activity of erlotinib on P-glycoprotein-mediated drug resistance is dependent upon the transporter substrate. These findings will be useful in understanding the pharmacological interactions of erlotinib used in combinational chemotherapy.
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PMID:Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib. 1949 73

Protein tyrosine kinases are enzymes which catalyze the phosphorylation of tyrosine residues and activate a downstream cascade of cellular signalling pathways which regulate cell proliferation, differentiation and apoptosis and a wide variety of cellular functions. Clinical developments over the past decade have identified several novel therapeutic agents which inhibit tyrosine kinase activity, either by direct receptor inhibition or indirect inhibition of tyrosine kinase controlled pathways. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), such as gefitinib and erlotinib have been studied extensively in patients with refractory non-small cell lung cancer (NSCLC). Early studies with gefitinib showed undoubted clinical activity but failed to show a survival benefit, whereas studies with erlotinib showed a small but statistically significant benefit in overall survival. Subsequent studies explored the possibility of synergistic activity between targeted agents (gefitinib or erlotinib) and conventional chemotherapy drugs reporting disappointing results. Clinical trial results with gefitinib and erlotinib, either as monotherapy or in combination with chemotherapy, have failed to match the encouraging results noted in the pre-clinical setting. It is now increasingly recognised that clinical exploration of molecular targeted agents may not conform well to traditional phase I/II/III drug trial designs. Therapeutic responses may be limited to a small subpopulation of patients, therefore diluting the overall therapeutic effect. Hypothesising a genetic basis for the heterogeneity in trial results, biomarkers (such as EGFR gene mutation analysis, EGFR protein expression, and increased EGFR gene copy number) have been studied with a view to identifying a target population most likely to benefit from these drugs. Future clinical trials with targeted agents need to be carefully designed to incorporate correlative translational research elements that will allow selection of appropriate treatment strategies for individual patients. For assessment of phase III trial results in advanced disease, progression free survival may serve as a more appropriate end-point than response rate in an adequately designed trial in the appropriately selected population, although there should be no substitute for the overall survival and quality of life end points. The role of EFGR TKI in NSCLC will be discussed in detail and data from these studies will be used to illustrate the challenges in designing clinical trials and interpreting outcomes.
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PMID:Role of tyrosine kinase inhibitors in lung cancer. 1951 98

Epidermal growth factor receptor inhibitors (EGFRIs) are new anticancer agents that act by inhibiting EGFR signaling transduction pathways, thus decreasing tumor growth. In more than 30 countries, EGFRIs are currently used in the treatment of a number of solid tumors, and other indications are being sought. In the United States, select EGFRIs have been approved in certain patients with non-small cell lung cancer, metastatic colorectal carcinoma, and advanced squamous cell carcinoma of the head and neck. Various cutaneous side effects of EGFRIs have been reported, including acneiform eruptions, chronic paronychia, xerosis, a seborrheic dermatitis-like eruption, changes in hair texture, and nonscarring alopecia. We present a 60-year-old woman with non-small cell lung cancer who developed a persistent generalized itchy eruption and progressive nonscarring alopecia shortly after initiation of erlotinib (Tarceva). Scalp biopsy showed near-equal number of anagen and catagen/telogen hair follicles, and a superficial and deep perivascular lymphoplasmocytic infiltration. These changes are typical of the nonscarring alopecia induced by EGFRIs. Because it is likely that EGFRIs will be increasingly used, dermatopathologists are likely to see more reactions from these agents. Familiarity with their side effects is essential to accurate diagnosis and effective patient management.
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PMID:A case report of inflammatory nonscarring alopecia associated with the epidermal growth factor receptor inhibitor erlotinib. 1951 75

Epidermal growth factor receptor (EGFR)-mediated signaling helps regulate bone development and healing through its effects on osteogenic cells. Here, we show how EGFR activity and osteogenic differentiation responses in primary human bone marrow-derived multipotent stromal cells (MSCs) are influenced by presenting covalently tethered epidermal growth factor (tEGF) on the culture substratum, a presentation mode that reduces EGFR internalization and restricts signaling to the cell surface. In both absence and presence of tEGF, MSCs increase expression levels of EGFR and its heterodimerization partner HER2 during the course of osteogenic differentiation. tEGF substrata increased levels of phosphorylated EGFR and phosphorylated extracellular regulated kinase (ERK) compared to control substrata, and these elevations were associated with a twofold enhancement of MSC alkaline phosphatase activity at day 7 and matrix mineralization at day 21. Surprisingly, addition of soluble EGF (sEGF) to cells cultured on tEGF substrata reduces osteogenic differentiation, even though EGFR signaling is more strongly activated in acute, short-term manner by sEGF treatment than by tEGF treatment. A striking concomitant result of the sEGF effects is near-complete downregulation of EGFR and HER2, demonstrating that the tEGF/EGFR interaction is dynamically reversible even though temporally sustained. Taken together, our results show that enhanced MSC osteogenic differentiation corresponds to a sustained combination of receptor expression and ligand presentation, both of which are maintained by tEGF.
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PMID:Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi-potent marrow stromal cells. 1954 88

Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.
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PMID:Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. 1968 Feb 94

Epidermal growth factor receptor kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 occurs frequently in breast, ovarian, and lung cancers, making it an important therapeutic target in the treatment of cancer. Blocking HER2-mediated signaling with antibodies or small molecules has been shown to be effective in inhibiting cell growth. After analyzing the crystal structure of the HER2-herceptin complex, several peptidomimetics (HERP5, 6, and 7) were designed to inhibit HER2-mediated signaling for cell growth. We have used an in silico screening method to investigate the chemical diversity of the designed compounds. autodock software was used to dock the different analogs of HERP5 and HERP7 with HER2 protein extracellular domain. A total of 53 compounds were docked to HER2 protein, and their binding modes were analyzed in terms of docking energy, hydrogen bonding, and hydrophobic interactions. Compounds that exhibited low-energy docked structures were chosen for chemical synthesis and biological activity. Two of the compounds (HERP5 and HERP7) exhibited antiproliferative activity, with IC(50) values of 0.396 microm and 0.143 microm, respectively, against SKBR-3 cell lines (breast cancer cell lines) that overexpress HER2 protein.
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PMID:Design, synthesis, and docking studies of peptidomimetics based on HER2-herceptin binding site with potential antiproliferative activity against breast cancer cell lines. 1970 26

High prevalence of squamous anal lesions is linked to oncogenic human papillomavirus (HPV). Human immunodeficiency virus (HIV) promotes anal carcinogenesis. Epidermal growth factor receptor (EGFR), HER2/neu, c-Met, and vascular endothelial growth factor receptor-1 (VEGFR1) (tyrosine kinase growth factor receptors) are implicated in tumor progression, but little is known about their role in anal lesions. We investigated their expression and distribution in normal, dysplastic, and carcinomatous anal epithelium and then tried to analyze the effects on these variables of HPV and the HIV-positive status. Seventy-one HIV-positive and 47 HIV-negative patients were selected. We studied growth factor receptors, p16 and Ki67 expression, by in situ hybridization, fluorescent in situ hybridization (FISH) and chromogen in situ hybridization (CISH), immunocytochemistry, and morphological quantification in 226 lesions, either infected by HPV6 and 11 (31 condylomas acuminata) or infected with oncogenic HPVs (48 invasive cancers, 147 anal intraepithelial neoplasias). No HER2/neu was detected. Strong EGFR immunolabeling was not accompanied by gene amplification. The number and intensity of EGFR- and c-Met-immunoreactive cells increased significantly during lesion progression, highlighting the effects of oncogenic HPVs. EGFR, c-Met, VEGFR1, and p16 were coexpressed in 96% of invasive cancers. HIV-modified c-Met expression in condyloma acuminata (P < .008) and invasive cancers (P < .02). Strong HIV-related immunodeficiency and an absence of antiretroviral therapy increased c-Met and/or EGFR expression. HIV-positive anal cancers showed correlated c-Met and VEGFR1 (P < .003), strong p16 labeling, and an increased Ki67 proliferation. The finding that EGFR, c-Met, and VEGFR1 involved in carcinogenesis are well-represented and coexpressed in anal cancers, especially in HIV-positive population, suggests possible novel targeted treatments for anal diseases.
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PMID:Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus. 1971 55

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), such as gefitinib or erlotinib, is mainly metabolized in liver. To date, the safety data on administrating EGFR-TKI to patients with liver dysfunction is quite limited. Here, we administered gefitinib to two adenocarcinoma patients with liver cirrhosis, and one patient with EGFR gene mutation in exon 21 achieved long stable disease (SD) without any toxicity. Pharmacokinetic data of alternate days administration in these patients were similar to those of daily administration in patients with normal liver function. Although further studies are needed, a reduced dose of gefitinib might be feasible for patients with liver dysfunction.
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PMID:Gefitinib for non-small cell lung cancer patients with liver cirrhosis. 1975 73

This is a study of 205 consecutive invasive breast carcinomas. The principal aim was to identify morphologic and immunohistochemical features of tumors that belong to the molecular class ERBB2. The invasive breast carcinomas were classified using semiquantitative immunohistochemical results for estrogen receptor (ER), progesterone receptor, (PR), and HER2 into following classes: Luminal A (strong ER+, HER2 negative), Luminal B (weak to moderate ER/PR+, HER2 negative), Triple Negative (TN; ER/PR negative, HER2 negative), ERBB2 (ER/PR negative, HER2 positive), Luminal A-HER2 Hybrid (strong ER+, HER2 positive), Luminal B-HER2 Hybrid (weak to moderate ER/PR+, HER2 positive). Of the 205 tumors, 113 (55%) were classified as Luminal A, 34 (17%) as Luminal B, 32 (15%) as TN, 8 (4%) as ERBB2, 10 (5%) as Luminal A-HER2 Hybrid, and 8 (4%) as Luminal B-HER2 Hybrid. Majority of the ERBB2 tumors were high grade as expected, with average Nottingham score of 8. Moderate lymphoid infiltrate (constituting 25% to 50% of the tumor) was seen in 5 of 8 (63%) cases and necrosis in 3 of 8 (38%) cases. The most striking morphologic feature associated with ERBB2 tumors was the presence of apocrine differentiation seen in 7 of 8 (88%) cases. CK5 immunoreactivity was seen in 5 of 8 cases (63%). Epidermal growth factor receptor staining with 2+ or 3+ score was also seen in 5 cases (63%). Due to low prevalence of ERBB2 tumors, additional data set of 191 cases enriched in ERBB2 and TN tumors was used for confirmation of morphologic findings. We conclude that tumors with apocrine differentiation are most often of ERBB2 type. ERBB2 tumors demonstrate some features classically ascribed to TN basal-like tumors. Epidermal growth factor receptor overexpression in ERBB2 tumors may have additional predictive value.
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PMID:Breast cancer molecular class ERBB2: preponderance of tumors with apocrine differentiation and expression of basal phenotype markers CK5, CK5/6, and EGFR. 1980 38


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