Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.

Nature
Authors
Keywords
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.

Year of Publication
2009
Journal
Nature
Volume
462
Issue
7269
Pages
108-12
Date Published
2009 Nov 05
ISSN
1476-4687
URL
DOI
10.1038/nature08460
PubMed ID
19847166
PubMed Central ID
PMC2783335
Links
Grant list
R01 CA130988-01A2 / CA / NCI NIH HHS / United States
R33 CA128625 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R01 CA130988 / CA / NCI NIH HHS / United States
R33 CA128625-01A1 / CA / NCI NIH HHS / United States
R33 CA128625-02 / CA / NCI NIH HHS / United States
T32 CA09172-33 / CA / NCI NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
R01 CA129105-03 / CA / NCI NIH HHS / United States