Human Gene Set: KRAS.600_UP.V1_DN


Standard name KRAS.600_UP.V1_DN
Systematic name M2880
Brief description Genes down-regulated in four lineages of epithelial cell lines over-expressing an oncogenic form of KRAS [GeneID=3845] gene.
Full description or abstract 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. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain 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 c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
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 vs AALE-Vector: top 300 genes (diff. of means)
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Source species Homo sapiens
Contributed by Pablo Tamayo (Broad Institute)
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