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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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Poulikakos PI Persaud Y Janakiraman M Kong X Ng C Moriceau G Shi H Atefi M Titz B Gabay MT Salton M Dahlman KB Tadi M Wargo JA Flaherty KT Kelley MC Misteli T Chapman PB Sosman JA Graeber TG Ribas A Lo RS Rosen N Solit DB 《Nature》2011,480(7377):387-390
Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner. 相似文献
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Ingrid Dahlman Iain A Eaves Roman Kosoy V Anne Morrison Joanne Heward Stephen C L Gough Amit Allahabadia Jayne A Franklyn Jaakko Tuomilehto Eva Tuomilehto-Wolf Francesco Cucca Cristian Guja Constantin Ionescu-Tirgoviste Helen Stevens Philippa Carr Sarah Nutland Patricia McKinney Julian P Shield William Wang Heather J Cordell Neil Walker John A Todd Patrick Concannon 《Nature genetics》2002,30(2):149-150
It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable. 相似文献
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Ueda H Howson JM Esposito L Heward J Snook H Chamberlain G Rainbow DB Hunter KM Smith AN Di Genova G Herr MH Dahlman I Payne F Smyth D Lowe C Twells RC Howlett S Healy B Nutland S Rance HE Everett V Smink LJ Lam AC Cordell HJ Walker NM Bordin C Hulme J Motzo C Cucca F Hess JF Metzker ML Rogers J Gregory S Allahabadia A Nithiyananthan R Tuomilehto-Wolf E Tuomilehto J Bingley P Gillespie KM Undlien DE Rønningen KS Guja C Ionescu-Tîrgovişte C Savage DA Maxwell AP Carson DJ Patterson CC Franklyn JA 《Nature》2003,423(6939):506-511
Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction. 相似文献
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Summary Caution must be taken in the prevelant use of the pentacyanoammonioferrate reagent for the detection of L-canavanine in biological materias. This reagent reacts with L-histidine at neutral pH to form a pentacyanoammonioferate-histidine complex that is mistaken readily for its canavanine-containing counterpart.This work was supported by a grant from the National Science Foundation (PCM-78-20167). This is publication number 81-7-199 of the Kentucky Agriculatural Experiment Station, Lexington 相似文献
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