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EGFR Pathway (egfr + pathway)
Selected AbstractsAmphiregulin is a factor for resistance of glioma cells to cannabinoid-induced apoptosisGLIA, Issue 13 2009Mar Lorente Abstract Gliomas, one of the most malignant forms of cancer, exhibit high resistance to conventional therapies. Identification of the molecular mechanisms responsible for this resistance is therefore of great interest to improve the efficacy of the treatments against these tumors. ,9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the ability of these compounds to induce apoptosis of tumor cells. By analyzing the gene expression profile of two sub-clones of C6 glioma cells with different sensitivity to cannabinoid-induced apoptosis, we found a subset of genes with a marked differential expression in the two sub-clones. Furthermore, we identified the epidermal growth factor receptor ligand amphiregulin as a candidate factor to mediate the resistance of glioma cells to cannabinoid treatment. Amphiregulin was highly overexpressed in the cannabinoid-resistant cell line, both in culture and in tumor xenografts. Moreover, in vivo silencing of amphiregulin rendered the resistant tumors xenografts sensitive to cannabinoid antitumoral action. Amphiregulin expression was associated with increased extracellular signal-regulated kinase (ERK) activation, which mediated the resistance to THC by blunting the expression of p8 and TRB3,two genes involved in cannabinoid-induced apoptosis of glioma cells. Our findings therefore identify Amphirregulin as a factor for resistance of glioma cells to THC-induced apoptosis and contribute to unraveling the molecular bases underlying the emerging notion that targeted inhibition of the EGFR pathway can improve the efficacy of antitumoral therapies. © 2009 Wiley-Liss, Inc. [source] Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinibINTERNATIONAL JOURNAL OF CANCER, Issue 12 2008Tiziana Servidei Abstract Deregulated signaling through the epidermal growth factor receptor (EGFR) is involved in chemoresistance. To identify the molecular determinants of sensitivity to the EGFR inhibitor gefitinib (Iressa, ZD1839) in chemoresistance, we compared the response of matched chemosensitive and chemoresistant glioma and ovarian cancer cell lines. We found that chemoresistant cell lines were 2- to 3-fold more sensitive to gefitinib growth-inhibitory effects, because of decreased proliferation rather than survival. Sensitivity to gefitinib correlated with overexpression and constitutive phosphorylation of HER2 and HER3, but not EGFR, altered HER ligand expression, and enhanced activation of EGF-triggered EGFR pathway. No activating mutations were found in EGFR. Gefitinib fully inhibited EGF-induced and constitutive Akt activation only in chemoresistant cells. In parallel, gefitinib downregulated constitutively phosphorylated HER2 and HER3, and activated GSK3, with a concomitant degradation of cyclin D1. Ectopically overexpressed HER2 on its own was insufficient to sensitize chemonaive cells to gefitinib. pHER3 coimmunoprecipitated with p85-PI3K in chemoresistant cells and gefitinib dissociated these complexes. siRNA-mediated inhibition of HER3 decreased constitutive activation of Akt and sensitivity to gefitinib in chemoresistant cells. Our study indicates that in chemoresistant cells gefitinib inhibits both an enhanced EGF-triggered pathway and a constitutive HER3-mediated Akt activation, indicating that inhibition of HER3 together with that of EGFR could be relevant in chemorefractory tumors. Furthermore, in combination experiments gefitinib enhanced the effects of coadministered drugs more in chemoresistant than chemosensitive ovarian cancer cells. Combined treatment might be therapeutically beneficial in chemoresistant tumors from ovary and likely from other tissues. © 2008 Wiley-Liss, Inc. [source] Activation of epidermal growth factor receptors in astrocytes: From development to neural injuryJOURNAL OF NEUROSCIENCE RESEARCH, Issue 16 2007Bin Liu Abstract The epidermal growth factor receptor (EGFR) pathway controls the phenotypic characteristics of astrocytes. In the developing central nervous system (CNS), activation of the EGFR pathway induces astrocyte differentiation, forming the cribriform structure that surrounds axons and providing a supportive environment for neurons. In the adult CNS, the EGFR pathway is absent from astrocytes but is highly up-regulated and activated following neuronal injury. Activation of the EGFR pathway triggers quiescent astrocytes to become reactive astrocytes. Although astrocytes regulated by the EGFR pathway play constructive roles in the developing CNS, astrocytes that become reactive in response to activation of the EGFR pathway appear to be destructive to neurons in the adult CNS. The reappearance and activation of EGFRs in astrocytes under pathological conditions may activate a developmental process in an adult tissue. Regulation of EGFR function in astrocytes may be a new therapeutic strategy for the treatment of neural disorders. © 2007 Wiley-Liss, Inc. [source] Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancerCANCER SCIENCE, Issue 12 2007Tetsuya Mitsudomi Recent discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma greatly stimulated biomarker research on predictive factors for EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. Although patients with activating mutations of the EGFR generally respond to EGFR TKIs very well, it is natural to assume that there is no sole determinant, considering great complexity and redundancy of the EGFR pathway. Subsequently, roles of different types of EGFR mutations or mutations of genes that are members of the EGFR pathway such as KRAS and HER2 have been evaluated. In this review, we summarize the recent findings about how mutations of the EGFR and related genes affect sensitivity to EFGR-TKIs. We also discuss molecular mechanisms of acquired resistance to EGFR-TKIs that is almost inevitable in EGFR-TKI therapy. The door for genotype-based treatment of lung cancer is beginning to open, and through these efforts, it will be possible to slow the progression of lung cancer and eventually, to decrease mortality from lung cancer. (Cancer Sci 2007; 98: 1817,1824) [source] Targeted inhibition of the EGFR pathways enhances Zn-BC-AM PDT-induced apoptosis in well-differentiated nasopharyngeal carcinoma cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2009Ho-Kee Koon Abstract Epidermal growth factor receptor (EGFR), a receptor often expressed in nasopharyngeal carcinoma (NPC) cells, is one of the recently identified molecular targets in cancer treatment. In the present study, the effects of combined treatment of Zn-BC-AM PDT with an EGFR inhibitor AG1478 were investigated. Well-differentiated NPC HK-1 cells were subjected to PDT with 1,µM of Zn-BC-AM and were irradiated at a light dose of 1,J/cm2 in the presence or absence of EGFR inhibitor AG1478. Specific protein kinase inhibitors of downstream EGFR targets were also used in the investigation. EGFR, Akt, and ERK were found constitutively activated in HK-1 cells and the activities could be inhibited by the EGFR inhibitor AG1478. A sub-lethal concentration of AG1478 was found to further enhance the irreversible cell damage induced by Zn-BC-AM PDT in HK-1 cells. Pre-incubation of the cells with specific inhibitors of EGFR (AG1478), PI3k/Akt (LY294002), or MEK/ERK (PD98059) before light irradiation were found to enhance Zn-BC-AM PDT-induced formation of apoptotic cells. The efficacy of Zn-BC-AM PDT can be increased through the inhibition of EGFR/PI3K/Akt and EGFR/MEK/ERK signaling pathways in NPC cells. Combination therapy with Zn-BC-AM PDT and EGFR inhibitors may further be developed for the treatment of advanced NPC. J. Cell. Biochem. 108: 1356,1363, 2009. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||