165 AZD2171, a potent VEGF receptor tyrosine kinase inhibitor, combined with mechanistically distinct antitumor therapies in vivo
Stephen R. WedgeJane KendrewPaula J. ValentineSandra R. BraveS. BarnettJ.M. JürgensmeierLaurent HennequinDJ Ogilvie
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Because conventional chemotherapy is not specific for cancer cells leading to toxic side effects there is a need for novel agents with high grade antitumor specificity. The major prerequisite to develop such drugs is to understand the targets that these agents should attack. In recent years a number of promising new anticancer drugs have been developed which target intracellular pathways or extracellular cell molecules. The clinically most effective compounds function as tyrosine kinase inhibitors. In the past, various tyrosine kinase receptors have been identified as regulators of tumor or tumor vessel growth. Having shown their expression characteristics in different tumor entities, specific inhibitors of the ATP binding sites of these receptors or antibodies were developed and entered clinical trials. The pathognomonic role of the tyrosine kinase defines the way of action of the inhibiting drug, whereas the amount of expression in tumor tissue defines the rationale to use the inhibitor to treat a specific protein. The future will define indications for such drugs by tumor kinase profiles instead of tumor entities. Gleevec, inhibiting the BCR-ABL tyrosine kinase; Iressa, inhibiting the EGF-receptor tyrosine kinase, Herceptin, inhibiting the Her2 / neu tyrosine kinase and PTK787 / ZK222584, inhibiting the VEGF-receptor tyrosine kinase will be discussed as representatives of selective tyrosine kinase inhibitors whereas ZD6474 and SU6668 will be discussed as representatives of multitarget tyrosine kinase inhibitors. Keywords: tyrosine kinases, receptor tyrosine kinase, anti cancer, vegf-receptor, egf-receptor
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Receptor tyrosine kinase–like orphan receptor 2 is an enzyme-linked receptor which specifically modulates WNT5A signaling and plays an important role in tumorigenesis, invasion, and metastasis; however, the precise role of receptor tyrosine kinase–like orphan receptor 2 in cancer is controversial. The purpose of this study was to investigate the expression and role of receptor tyrosine kinase–like orphan receptor 2 in ovarian carcinoma and clarify the biological functions and interactions of receptor tyrosine kinase–like orphan receptor 2 with non-canonical Wnt pathways in ovarian cancer. The result of the human ovary tissue microarray revealed that the receptor tyrosine kinase–like orphan receptor 2–positive rate increased in malignant epithelial ovarian cancers and was extremely higher in the metastatic tumor tissues, which was also higher than that in the malignant ovarian tumor tissues. In addition, high expression of receptor tyrosine kinase–like orphan receptor 2 was closely related with ovarian cancer grading. The expression of receptor tyrosine kinase–like orphan receptor 2 protein was higher in SKOV3 and A2780 cells than OVCAR3 and 3AO cells. Knockdown of receptor tyrosine kinase–like orphan receptor 2 inhibited ovarian cancer cell proliferation, migration, invasion, and induced morphologic as well as digestive state alterations in stably transfected SKOV3 cells. Detailed study further revealed that silencing of receptor tyrosine kinase–like orphan receptor 2 reversed the epithelial–mesenchymal transition and inhibited non-canonical Wnt signaling. Our findings suggest that receptor tyrosine kinase–like orphan receptor 2 may be an important regulator of epithelial–mesenchymal transition, primarily regulated the non-canonical Wnt signaling pathway in ovarian cancer cells, and may display a promising therapeutic target for ovarian cancer.
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Receptor tyrosine kinase c-Met is encoded by c-Met proto-oncogene. It plays an important role in cell growth,invasion,anti-apoptosis,and other biological effects. The abnormal expression of c-Met is closely related with the development and malignant biological behaviour of lung cancer. The targeted therapy for c-Met pathway is the new hot spot of lung cancer treatment. This paper reviews biological characteristics of receptor tyrosine kinase c-Met,its relationship with lung cancer,and the application in treatment of lung cancer.
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Proto-oncogene; Mutation; Lung cancer; Receptor ; Targeted therapy
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Tyrosine kinases have significant roles in cell growth, apoptosis, development, and disease. To explore the use of zebrafish as a vertebrate model for tyrosine kinase signaling and to better understand their roles, we have identified all of the tyrosine kinases encoded in the zebrafish genome and quantified RNA expression of selected tyrosine kinases during early development. Using profile hidden Markov model analysis, we identified 122 zebrafish tyrosine kinase genes and proposed unambiguous gene names where needed. We found them to be organized into 39 nonreceptor and 83 receptor type, and 30 families consistent with human tyrosine kinase family assignments. We found five human tyrosine kinase genes (epha1, bmx, fgr, srm, and insrr) with no identifiable zebrafish ortholog, and one zebrafish gene (yrk) with no identifiable human ortholog. We also found that receptor tyrosine kinase genes were duplicated more often than nonreceptor tyrosine kinase genes in zebrafish. We profiled expression levels of 30 tyrosine kinases representing all families using direct digital detection at different stages during the first 24 hours of development. The profiling experiments clearly indicate regulated expression of tyrosine kinases in the zebrafish, suggesting their role during early embryonic development. In summary, our study has resulted in the first comprehensive description of the zebrafish tyrosine kinome.
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HAMP domain
ERBB3
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Abstract : Receptor tyrosine kinases are important in cell signal transduction and proliferation. Abnormal expression of tyrosine kinases often leads to malignant transformation. C-met is a tyrosine kinase receptor and its ligand is hepatocyte growth factor (HGF). HGF/c-met plays diverse role in regulation of cell growth, shape and movement. Constitutively activated met, such as tpr-met, is a potent oncogene in vitro, but its carcinogenic role in vivo remains unclear. Our study demonstrates that expression of tpr-met leads to development of mammary tumors and other malignancies in transgenic mice, and suggests that deregulated met expression may be involved in mammary carcinogenesis.
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Purpose of review Extensive evidence indicates that receptor tyrosine kinases and nonreceptor tyrosine kinases underlie vascular damage in hypertension. However, recent clinical studies using vascular endothelial growth factor (VEGF) receptor inhibitors (bevacizumab, axitinib) revealed the unexpected finding of increased blood pressure. Whether this is a generalized receptor tyrosine kinase phenomenon or a VEGF receptor-specific effect is unclear. The present review focuses on current findings regarding the role of tyrosine kinases and signaling in vascular pathobiology of hypertension. Recent findings Multiple complex and interacting signaling pathways activated by receptor and nonreceptor tyrosine kinases are upregulated and have been implicated in vascular alterations associated with high blood pressure. Experimental evidence suggests that receptor tyrosine kinase activation by direct ligand binding as well as by ligand-independent mechanisms through transactivation by G protein-coupled receptors plays a role in vascular signaling and cardiovascular diseases. Summary Cellular mechanisms and signaling pathways mediated by tyrosine kinases involved in hypertensive vascular damage are currently the subject of intensive investigation. The unexpected finding of hypertension as a side effect in patients treated with VEGF receptor inhibitors suggests that some tyrosine kinases negatively regulate vascular function. Further characterization of these processes will provide greater understanding of the role of tyrosine kinases in vascular pathobiology in hypertension and should provide new insights on novel therapeutic targets.
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Abstract Novel high-throughput analyses in molecular biology allow sensitive and rapid identification of disease-related genes and drug targets. We have used quantitative real-time reverse transcription-PCR reactions (n = 23,000) to analyze expression of all human receptor tyrosine kinases (n = 56) in malignant tumors (n = 313) of different origins and normal control samples (n = 58). The different tumor types expressed very different numbers of receptor tyrosine kinases: whereas brain tumors and testicular cancer expressed 50 receptor tyrosine kinases, acute myeloid leukemia (AML) samples expressed only 20 different ones. Specimens of similar tumor origin exhibited characteristic receptor tyrosine kinase expression patterns and were grouped together in hierarchical cluster analyses. When we focused on specific tumor entities, receptor tyrosine kinases were identified that were disease and/or stage specific. Leukemic blasts from AML bone marrow samples differed significantly in receptor tyrosine kinase expression compared with normal bone marrow and purified CD34+ cells. Among the differentially expressed receptor tyrosine kinases, we found FLT3, c-kit, CSF1 receptor, EPHB6, leukocyte tyrosine kinase, and ptk7 to be highly overexpressed in AML samples. Whereas expression changes of some of these were associated with altered differentiation patterns (e.g., CSF1 receptor), others, such as FLT3, were genuinely overexpressed in leukemic blasts. These data and the associated database (http://medweb.uni-muenster.de/institute/meda/research/) provide a comprehensive view of receptor tyrosine kinase expression in human cancer. This information can assist in the definition of novel drug targets.
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