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Bivona TG Hieronymus H Parker J Chang K Taron M Rosell R Moonsamy P Dahlman K Miller VA Costa C Hannon G Sawyers CL 《Nature》2011,471(7339):523-526
Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs), but the magnitude of tumour regression is variable and transient. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence. 相似文献
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Zhang Z Lee JC Lin L Olivas V Au V LaFramboise T Abdel-Rahman M Wang X Levine AD Rho JK Choi YJ Choi CM Kim SW Jang SJ Park YS Kim WS Lee DH Lee JS Miller VA Arcila M Ladanyi M Moonsamy P Sawyers C Boggon TJ Ma PC Costa C Taron M Rosell R Halmos B Bivona TG 《Nature genetics》2012,44(8):852-860
Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer. 相似文献
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A synthetic peptide as an antagonist of substance P 总被引:1,自引:0,他引:1
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Zusammenfassung Es wurden eine Reihe von Phenothiazin-Derivaten auf ihr Vermögen die H3-Noradrenalinaufnahme in das Rattenherz zu blockieren getestet. Dabei hat sich ergeben, dass dieses Blockierungsvermögen weniger mit den antimotorischen oder Antihistamineigenschaften der Substanzen gekoppelt zu sein scheint, sondern eher mit deren antiadrenergischen Wirkungskomponenten. 相似文献
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Zusammenfassung Aktivitätserhöhung im sympathischen Nervensystem bei Katzen wurde durch Inhalieren von 25% CO2 in O2 hervorgerufen. Es wurde der Einfluss erhöhter sympathischer Aktivität auf den Noradrenalingehalt sympathischer Nerven geprüft, welche zu motorischen Muskeln verlaufen. Hyperkapnia rief keine Veränderung im akut dezentralisierten M. Gastrocnemius hervor. Bei intaktem sympathischem Fluss zum Muskel bewirkte Hyperkapnia eine erhebliche Erniedrigung des Noradrenalingehaltes. Die Wirkung hängt somit von einem intakten sympathischen Ausfluss ab. 相似文献
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The first hominin of Europe 总被引:3,自引:0,他引:3
Carbonell E Bermúdez de Castro JM Parés JM Pérez-González A Cuenca-Bescós G Ollé A Mosquera M Huguet R van der Made J Rosas A Sala R Vallverdú J García N Granger DE Martinón-Torres M Rodríguez XP Stock GM Vergès JM Allué E Burjachs F Cáceres I Canals A Benito A Díez C Lozano M Mateos A Navazo M Rodríguez J Rosell J Arsuaga JL 《Nature》2008,452(7186):465-469
The earliest hominin occupation of Europe is one of the most debated topics in palaeoanthropology. However, the purportedly oldest of the Early Pleistocene sites in Eurasia lack precise age control and contain stone tools rather than human fossil remains. Here we report the discovery of a human mandible associated with an assemblage of Mode 1 lithic tools and faunal remains bearing traces of hominin processing, in stratigraphic level TE9 at the site of the Sima del Elefante, Atapuerca, Spain. Level TE9 has been dated to the Early Pleistocene (approximately 1.2-1.1 Myr), based on a combination of palaeomagnetism, cosmogenic nuclides and biostratigraphy. The Sima del Elefante site thus emerges as the oldest, most accurately dated record of human occupation in Europe, to our knowledge. The study of the human mandible suggests that the first settlement of Western Europe could be related to an early demographic expansion out of Africa. The new evidence, with previous findings in other Atapuerca sites (level TD6 from Gran Dolina), also suggests that a speciation event occurred in this extreme area of the Eurasian continent during the Early Pleistocene, initiating the hominin lineage represented by the TE9 and TD6 hominins. 相似文献
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