Human Gene Set: TBK1.DN.48HRS_DN

Standard name TBK1.DN.48HRS_DN
Systematic name M2868
Brief description Genes down-regulated in epithelial lung cancer cell lines upon over-expression of an oncogenic form of KRAS [GeneID=3845] gene and knockdown of TBK1 [GeneID=29110] gene by RNAi.
Full description or abstract Profiling of immortalized human lung epithelial cells following oncogenic KRAS expression and TBK1 suppression. The purpose of the dataset is to analyze expression of genes induced by KRAS and regulated by TBK1. The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference (RNAi) to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkB kinase, TBK1, was selectively essential in cells that harbor mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving cREL and BCL-XL that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations identify TBK1 as a potential therapeutic target in KRAS mutant tumors and establish a general approach for the rational identification of co-dependent pathways in cancer. Knock out of TBK1 in the contect of KRAS activation (mutant) and control (WT).
Collection C6: Oncogenic Signature
Source publication Pubmed 19847166   Authors: Barbie DA,Tamayo P,Boehm JS,Kim SY,Moody SE,Dunn IF,Schinzel AC,Sandy P,Meylan E,Scholl C,Fröhling S,Chan EM,Sos ML,Michel K,Mermel C,Silver SJ,Weir BA,Reiling JH,Sheng Q,Gupta PB,Wadlow RC,Le H,Hoersch S,Wittner BS,Ramaswamy S,Livingston DM,Sabatini DM,Meyerson M,Thomas RK,Lander ES,Mesirov JP,Root DE,Gilliland DG,Jacks T,Hahn WC
Exact source AALE-KRAS + shTBK1 vs controls; top 1000 genes (diff. of means)
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Source species Homo sapiens
Contributed by Pablo Tamayo (Broad Institute)
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