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

被引：2568

作者：

Barbie, David A. ^{[1
,3
,4
,5
]}

Tamayo, Pablo ^{[3
,4
]}

Boehm, Jesse S. ^{[3
,4
]}

Kim, So Young ^{[1
,2
]}

Moody, Susan E. ^{[1
,3
,4
]}

Dunn, Ian F. ^{[1
,3
,4
,6
]}

Schinzel, Anna C. ^{[1
,3
,4
]}

Sandy, Peter ^{[8
,9
]}

Meylan, Etienne ^{[8
,9
]}

Scholl, Claudia ^{[7
]}

Froehling, Stefan ^{[7
]}

Chan, Edmond M. ^{[3
,4
]}

Sos, Martin L. ^{[10
,11
]}

Michel, Kathrin ^{[10
,11
]}

Mermel, Craig ^{[1
,3
,4
]}

Silver, Serena J. ^{[3
,4
]}

Weir, Barbara A. ^{[3
,4
]}

Reiling, Jan H. ^{[8
,12
]}

Sheng, Qing ^{[1
]}

Gupta, Piyush B. ^{[3
,4
]}

Wadlow, Raymond C. ^{[3
,4
,5
]}

Le, Hanh ^{[3
,4
]}

Hoersch, Sebastian ^{[9
]}

Wittner, Ben S. ^{[3
,4
,5
]}

Ramaswamy, Sridhar ^{[3
,4
,5
]}

Livingston, David M. ^{[1
]}

Sabatini, David M. ^{[3
,4
,8
,12
,13
]}

Meyerson, Matthew ^{[1
,2
,3
,4
]}

Thomas, Roman K. ^{[10
,11
,14
,15
,16
]}

Lander, Eric S. ^{[3
,4
,8
]}

Mesirov, Jill P. ^{[3
,4
]}

Root, David E. ^{[3
,4
]}

Gilliland, D. Gary ^{[1
,3
,4
,7
,13
]}

Jacks, Tyler ^{[3
,4
,8
,9
,13
]}

Hahn, William C. ^{[1
,2
,3
,4
,7
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[3] Broad Inst Harvard, Cambridge, MA 02142 USA

[4] MIT, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[6] Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA

[7] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[8] MIT, Dept Biol, Cambridge, MA 02139 USA

[9] Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA

[10] Max Planck Soc, Max Planck Inst Neurol Res, Klaus Joachim Zulch Labs, D-50931 Cologne, Germany

[11] Univ Cologne, Fac Med, D-50931 Cologne, Germany

[12] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[13] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[14] Univ Cologne, Ctr Integrated Oncol, D-50931 Cologne, Germany

[15] Univ Cologne, Dept Internal Med 1, D-50931 Cologne, Germany

[16] Max Planck Soc, Chem Genom Ctr, D-44227 Dortmund, Germany

来源：

NATURE | 2009年 / 462卷 / 7269期

基金：

芬兰科学院;

关键词：

NF-KAPPA-B; TUMOR-CELL SURVIVAL; LUNG ADENOCARCINOMA; ESSENTIAL GENES; K-RAS; ACTIVATION; SCREEN; PHOSPHORYLATION; CLASSIFICATION; APOPTOSIS;

D O I：

10.1038/nature08460

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1,2). Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical I kappa B 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-kappa B 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-kappa B signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.

引用

页码：108 / U122

页数：7