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Letter

Nature 462, 108-112 (5 November 2009) | doi:10.1038/nature08460; Received 23 January 2009; Accepted 27 August 2009; Published online 21 October 2009

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

David A. Barbie1,3,4, Pablo Tamayo3, Jesse S. Boehm3, So Young Kim1,2, Susan E. Moody1,3, Ian F. Dunn1,3,5, Anna C. Schinzel1,3, Peter Sandy7,8, Etienne Meylan7,8, Claudia Scholl6, Stefan Fröhling6, Edmond M. Chan3, Martin L. Sos9, Kathrin Michel9, Craig Mermel1,3, Serena J. Silver3, Barbara A. Weir3, Jan H. Reiling7,10, Qing Sheng1, Piyush B. Gupta3, Raymond C. Wadlow3,4, Hanh Le3, Sebastian Hoersch8, Ben S. Wittner3,4, Sridhar Ramaswamy3,4, David M. Livingston1, David M. Sabatini3,7,10,11, Matthew Meyerson1,2,3, Roman K. Thomas9,12,13, Eric S. Lander3,7, Jill P. Mesirov3, David E. Root3, D. Gary Gilliland1,3,6,11, Tyler Jacks3,7,8,11 & William C. Hahn1,2,3,6

  1. Department of Medical Oncology,
  2. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 USA
  3. Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
  4. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA
  5. Department of Neurosurgery,
  6. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
  7. Department of Biology, M.I.T., 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
  8. Koch Institute for Integrative Cancer Research, 40 Ames Street, Cambridge, Massachusetts 02142, USA
  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
  10. Whitehead Institute of Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
  11. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
  12. Department I of Internal Medicine and Center of Integrated Oncology, University of Köln, Gleueler Str. 50, 50931 Köln, Germany
  13. Chemical Genomics Center of the Max-Planck-Society, Otto-Hahn-Str. 15, 44227 Dortmund, Germany

Correspondence to: William C. Hahn1,2,3,6 Correspondence and requests for materials should be addressed to W.C.H. (Email: william_hahn@dfci.harvard.edu).

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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 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.

  1. Department of Medical Oncology,
  2. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 USA
  3. Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
  4. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA
  5. Department of Neurosurgery,
  6. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
  7. Department of Biology, M.I.T., 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
  8. Koch Institute for Integrative Cancer Research, 40 Ames Street, Cambridge, Massachusetts 02142, USA
  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
  10. Whitehead Institute of Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA
  11. Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA
  12. Department I of Internal Medicine and Center of Integrated Oncology, University of Köln, Gleueler Str. 50, 50931 Köln, Germany
  13. Chemical Genomics Center of the Max-Planck-Society, Otto-Hahn-Str. 15, 44227 Dortmund, Germany

Correspondence to: William C. Hahn1,2,3,6 Correspondence and requests for materials should be addressed to W.C.H. (Email: william_hahn@dfci.harvard.edu).