排序方式: 共有6条查询结果,搜索用时 15 毫秒
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TR Wilson J Fridlyand Y Yan E Penuel L Burton E Chan J Peng E Lin Y Wang J Sosman A Ribas J Li J Moffat DP Sutherlin H Koeppen M Merchant R Neve J Settleman 《Nature》2012,487(7408):505-509
Mutationally activated kinases define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance. The identification of resistance mechanisms has revealed a recurrent theme—the engagement of survival signals redundant to those transduced by the targeted kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstream cell-survival effectors—most notably, phosphatidylinositol-3-OH kinase (PI(3)K) and mitogen-activated protein kinase (MAPK). Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signalling output. Here, using a panel of kinase-'addicted' human cancer cell lines, we found that most cells can be rescued from drug sensitivity by simply exposing them to one or more RTK ligands. Among the findings with clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells. These observations highlight the extensive redundancy of RTK-transduced signalling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases. 相似文献
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Padiath QS Saigoh K Schiffmann R Asahara H Yamada T Koeppen A Hogan K Ptácek LJ Fu YH 《Nature genetics》2006,38(10):1114-1123
Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by symmetrical widespread myelin loss in the central nervous system, with a phenotype similar to chronic progressive multiple sclerosis. In this study, we identify a genomic duplication that causes ADLD. Affected individuals carry an extra copy of the gene for the nuclear laminar protein lamin B1, resulting in increased gene dosage in brain tissue from individuals with ADLD. Increased expression of lamin B1 in Drosophila melanogaster resulted in a degenerative phenotype. In addition, an abnormal nuclear morphology was apparent when cultured cells overexpressed this protein. This is the first human disease attributable to mutations in the gene encoding lamin B1. Antibodies to lamin B are found in individuals with autoimmune diseases, and it is also an antigen recognized by a monoclonal antibody raised against plaques from brains of individuals with multiple sclerosis. This raises the possibility that lamin B may be a link to the autoimmune attack that occurs in multiple sclerosis. 相似文献
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S Seshagiri EW Stawiski S Durinck Z Modrusan EE Storm CB Conboy S Chaudhuri Y Guan V Janakiraman BS Jaiswal J Guillory C Ha GJ Dijkgraaf J Stinson F Gnad MA Huntley JD Degenhardt PM Haverty R Bourgon W Wang H Koeppen R Gentleman TK Starr Z Zhang DA Largaespada TD Wu FJ de Sauvage 《Nature》2012,488(7413):660-664
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