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Cited by 3,890

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

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

Open access
Barbie, David A., Tamayo, Pablo, Boehm, Jesse S., Kim, So Young, Moody, Susan E., Dunn, Ian F., Schinzel, Anna C., Sandy, Peter, Meylan, Etienne, Scholl, Claudia, Fröhling, Stefan, Chan, Edmond M., Sos, Martin L., Michel, Kathrin, Mermel, Craig, Silver, Serena J., Weir, Barbara A., Reiling, Jan H., Sheng, Qing, Gupta, Piyush B., Wadlow, Raymond C., Le, Hanh, Hoersch, Sebastian, Wittner, Ben S., Ramaswamy, Sridhar, Livingston, David M., Sabatini, David M., Meyerson, Matthew, Thomas, Roman K., Lander, Eric S., Mesirov, Jill P., Root, David E., Gilliland, D. Gary, Jacks, Tyler, Hahn, William C.·2009·Nature
DOI 10.1038/nature08460
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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.

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Metadata

Authors
Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., Fröhling, S., Chan, E. M., Sos, M. L., Michel, K., Mermel, C., Silver, S. J., Weir, B. A., Reiling, J. H., Sheng, Q., Gupta, P. B., Wadlow, R. C., Le, H., Hoersch, S., Wittner, B. S., Ramaswamy, S., Livingston, D. M., Sabatini, D. M., Meyerson, M., Thomas, R. K., Lander, E. S., Mesirov, J. P., Root, D. E., Gilliland, D. G., Jacks, T., & Hahn, W. C.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2009-10-21
Volume
462
Issue
7269
Pages
108-112
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature08460
OpenAlex
W2123879591
Cited by
3,890
References
3
FWCI
28.69
Type
journal article
Language
en
Open access
bronze

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