Cyclin-dependent kinase 8

About: Cyclin-dependent kinase 8 is a research topic. Over the lifetime, 1405 publications have been published within this topic receiving 114161 citations. The topic is also known as: K35 & cyclin-dependent kinase 8.

Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.

Abstract: Background The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. Methods We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. Results Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rap...

BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.

Abstract: Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first-generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.

Review of epidermal growth factor receptor biology.

Abstract: The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that constitutes one of four members of the erbB family of tyrosine kinase receptors. Binding of EGFR to its cognate ligands leads to autophosphorylation of receptor tyrosine kinase and subsequent activation of signal transduction pathways that are involved in regulating cellular proliferation, differentiation, and survival. Although present in normal cells, EGFR is overexpressed in a variety of tumor cell lines and has been associated with poor prognosis and decreased survival. EGFR activation also plays a role in resistance to chemotherapy and radiation treatment in tumor cells. Over the past two decades, much effort has been directed at developing anticancer agents that can interfere with EGFR activity. The most common pharmacologic approaches to inhibiting EGFR have been to develop monoclonal antibodies and small-molecule inhibitors. Monoclonal antibodies block ligand binding to the extracellular domain, whereas the small-molecule inhibitors exert their effects at the intracellular portion of the receptor to prevent tyrosine kinase phosphorylation and subsequent activation of signal transduction pathways. A number of EGFR inhibitors have been developed that can arrest tumor growth and, in some cases, cause tumor regression. When used in combination with cytotoxic treatments, chemotherapy, and radiation, EGFR inhibitors have been able to potentiate their anticancer activity.

Notch signaling : Signal transduction

Abstract: The Notch/Lin-12/Glp-1 receptor family mediates the specification of numerous cell fates during development in Drosophila and Caenorhabditis elegans. Studies on the expression, mutant phenotypes, and developmental consequences of unregulated receptor activation have implicated these proteins in a general mechanism of local cell signaling, which includes interactions between equivalent cells and between different cell types. Genetic approaches in flies and worms have identified putative components of the signaling cascade, including a conserved family of extracellular ligands and two cellular factors that may associate with the Notch Intracellular domain. One factor, the Drosophila Suppressor of Hairless protein, is a DNA-binding protein, which suggests that Notch signaling may involve relatively direct signal transmission from the cell surface to the nucleus. Several vertebrate Notch receptors have also been discovered recently and play important roles in normal development and tumorigenesis