Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.
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.
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 USA.
David A
DA
Barbie
Pablo
P
Tamayo
Jesse S
JS
Boehm
So Young
SY
Kim
Susan E
SE
Moody
Ian F
IF
Dunn
Anna C
AC
Schinzel
Peter
P
Sandy
Etienne
E
Meylan
Claudia
C
Scholl
Stefan
S
Fröhling
Edmond M
EM
Chan
Martin L
ML
Sos
Kathrin
K
Michel
Craig
C
Mermel
Serena J
SJ
Silver
Barbara A
BA
Weir
Jan H
JH
Reiling
Qing
Q
Sheng
Piyush B
PB
Gupta
Raymond C
RC
Wadlow
Hanh
H
Le
Sebastian
S
Hoersch
Ben S
BS
Wittner
Sridhar
S
Ramaswamy
David M
DM
Livingston
David M
DM
Sabatini
Matthew
M
Meyerson
Roman K
RK
Thomas
Eric S
ES
Lander
Jill P
JP
Mesirov
David E
DE
Root
D Gary
DG
Gilliland
Tyler
T
Jacks
William C
WC
Hahn
D000483:Alleles; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D020869:Gene Expression Profiling; D005804:Genes, Lethal; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D020569:Proto-Oncogene Proteins c-rel; D051020:bcl-X Protein; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D015689:Oncogene Protein p21(ras)