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 allele1,2. 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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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

All microarray data are available from the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo) under accession codes GSE17671, GSE17672 and GSE17643.

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Acknowledgements

This work was supported in part by grants from the US National Cancer Institute (R33 CA128625, R01 CA130988) (W.C.H.) and NIH T32 CA09172-33 (D.A.B., S.E.M.), the Starr Cancer Consortium (I1-A11; W.C.H., D.G.G.), the Susan Madden Fund and an ASCO YIA (D.A.B.), a Department of Defense Prostate Cancer Postdoctoral Fellowship (S.Y.K.), a Brain Science Foundation Fellowship (I.F.D.), the Deutsche Krebshilfe (grant 107954) (R.K.T.), the Fritz-Thyssen-Stiftung (grant 10.08.2.175; R.K.T.) and the NGFNplus-program of the German Ministry of Science and Education (BMBF, grant 01GS08100; R.K.T.). We thank C. Yu, G. Wei and members of the Hahn laboratory for discussions. High-throughput RNAi screening was conducted at the RNAi Platform of the Broad Institute of MIT and Harvard.

Author Contributions D.A.B., J.S.B., S.Y.K., S.E.M. and W.C.H. designed the experiments. D.A.B. and P.T. performed computational analyses. S.Y.K., I.F.D., A.C.S., P.S., C.S., S.F., P.B.G., J.H.R., Q.S. and R.C.W. performed primary RNAi screens; S.J.S., S.H., B.S.W., C.M. and B.A.W. assisted with data analysis. D.A.B. performed secondary screen with help from H.L. S.E.M. performed tumour xenograft experiments. E.M. performed experiments with murine cell lines. D.A.B., J.S.B., E.M.C., M.L.S., K.M. and R.K.T. performed expression-profiling experiments. S.R., D.M.L., D.M.S., E.S.L., D.G.G., T.J. and D.E.R. supervised RNAi screens; M.M. and J.P.M. supervised data analysis. D.A.B. and W.C.H. wrote the manuscript. W.C.H. coordinated all aspects of the project. All authors discussed results and edited the manuscript.

Author information

Affiliations

  1. Department of Medical Oncology,

    • David A. Barbie
    • , So Young Kim
    • , Susan E. Moody
    • , Ian F. Dunn
    • , Anna C. Schinzel
    • , Craig Mermel
    • , Qing Sheng
    • , David M. Livingston
    • , Matthew Meyerson
    • , D. Gary Gilliland
    •  & William C. Hahn
  2. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 USA

    • So Young Kim
    • , Matthew Meyerson
    •  & William C. Hahn
  3. Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • David A. Barbie
    • , Pablo Tamayo
    • , Jesse S. Boehm
    • , Susan E. Moody
    • , Ian F. Dunn
    • , Anna C. Schinzel
    • , Edmond M. Chan
    • , Craig Mermel
    • , Serena J. Silver
    • , Barbara A. Weir
    • , Piyush B. Gupta
    • , Raymond C. Wadlow
    • , Hanh Le
    • , Ben S. Wittner
    • , Sridhar Ramaswamy
    • , David M. Sabatini
    • , Matthew Meyerson
    • , Eric S. Lander
    • , Jill P. Mesirov
    • , David E. Root
    • , D. Gary Gilliland
    • , Tyler Jacks
    •  & William C. Hahn
  4. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA

    • David A. Barbie
    • , Raymond C. Wadlow
    • , Ben S. Wittner
    •  & Sridhar Ramaswamy
  5. Department of Neurosurgery,

    • Ian F. Dunn
  6. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Claudia Scholl
    • , Stefan Fröhling
    • , D. Gary Gilliland
    •  & William C. Hahn
  7. Department of Biology, M.I.T., 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    • Peter Sandy
    • , Etienne Meylan
    • , Jan H. Reiling
    • , David M. Sabatini
    • , Eric S. Lander
    •  & Tyler Jacks
  8. Koch Institute for Integrative Cancer Research, 40 Ames Street, Cambridge, Massachusetts 02142, USA

    • Peter Sandy
    • , Etienne Meylan
    • , Sebastian Hoersch
    •  & Tyler Jacks
  9. Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Köln, Gleueler Str. 50, 50931 Köln, Germany

    • Martin L. Sos
    • , Kathrin Michel
    •  & Roman K. Thomas
  10. Whitehead Institute of Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Jan H. Reiling
    •  & David M. Sabatini
  11. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

    • David M. Sabatini
    • , D. Gary Gilliland
    •  & Tyler Jacks
  12. Department I of Internal Medicine and Center of Integrated Oncology, University of Köln, Gleueler Str. 50, 50931 Köln, Germany

    • Roman K. Thomas
  13. Chemical Genomics Center of the Max-Planck-Society, Otto-Hahn-Str. 15, 44227 Dortmund, Germany

    • Roman K. Thomas

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Competing interests

W.C.H., M.M. and D.M.L. are consultants for Novartis Pharmaceuticals, Inc.

Corresponding author

Correspondence to William C. Hahn.

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https://doi.org/10.1038/nature08460

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