Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Name
Jacks_Systematic RNA.pdf
Size
2.17 MB
Format
Adobe PDF
Checksum (MD5)
99fce341a213f512f0d1c240b1d0f2ca
Author(s)
Sandy, Peter
Meylan, Etienne
Reiling, Jan H.
Hoersch, Sebastian
Barbie, David A.
Tamayo, Pablo
Boehm, Jesse S.
Kim, So Young
Moody, Susan E.
Dunn, Ian F.
Date Issued
October 2009
Journal
Nature
Publisher
Nature Publishing Group
Citation
Barbie, David A., Pablo Tamayo, Jesse S. Boehm, So Young Kim, Susan E. Moody, Ian F. Dunn, Anna C. Schinzel, et al. “Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.” Nature 462, no. 7269 (October 21, 2009): 108-112.
Version
Author's final manuscript
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 IκB 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-κB 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-κB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike 3.0
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/nature08460
