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

David A. Barbie, Pablo Tamayo, Jesse S. Boehm, So Young Kim, Susan E. Moody, Ian F. Dunn, Anna C. Schinzel, Peter Sandy, Etienne Meylan, Claudia Scholl, Stefan Fröhling, Edmond M. Chan, Martin L. Sos, Kathrin Michel, Craig Mermel, Serena J. Silver, Barbara A. Weir, Jan H. Reiling, Qing Sheng, Piyush B. Gupta, Raymond C. Wadlow, Hanh Le, Sebastian Hoersch, Ben S. Wittner, Sridhar Ramaswamy, David M. Livingston, David M. Sabatini, Matthew Meyerson, Roman K. Thomas, Eric S. Lander, Jill P. Mesirov, David E. Root, D. Gary Gilliland, Tyler Jacks and William C. Hahn ()
Additional contact information
David A. Barbie: Department of Medical Oncology,
Pablo Tamayo: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Jesse S. Boehm: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
So Young Kim: Department of Medical Oncology,
Susan E. Moody: Department of Medical Oncology,
Ian F. Dunn: Department of Medical Oncology,
Anna C. Schinzel: Department of Medical Oncology,
Peter Sandy: M.I.T., 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Etienne Meylan: M.I.T., 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Claudia Scholl: Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
Stefan Fröhling: Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
Edmond M. Chan: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Martin L. Sos: 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
Kathrin Michel: 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
Craig Mermel: Department of Medical Oncology,
Serena J. Silver: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Barbara A. Weir: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Jan H. Reiling: M.I.T., 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
Qing Sheng: Department of Medical Oncology,
Piyush B. Gupta: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Raymond C. Wadlow: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Hanh Le: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Sebastian Hoersch: Koch Institute for Integrative Cancer Research, 40 Ames Street, Cambridge, Massachusetts 02142, USA
Ben S. Wittner: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Sridhar Ramaswamy: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
David M. Livingston: Department of Medical Oncology,
David M. Sabatini: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Matthew Meyerson: Department of Medical Oncology,
Roman K. Thomas: 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
Eric S. Lander: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
Jill P. Mesirov: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
David E. Root: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
D. Gary Gilliland: Department of Medical Oncology,
Tyler Jacks: Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
William C. Hahn: Department of Medical Oncology,

Nature, 2009, vol. 462, issue 7269, 108-112

Abstract: Targeting KRAS cancers Mutations in genes of the RAS family are preset on about 20% of human cancers, making RAS proteins prime potential targets for cancer therapy. Direct targeting of RAS proteins has not so far been productive, but two papers published in this issue offer the prospect of alternative targets in a signalling pathway downstream of RAS. Using a synthetic lethality RNAi screen, Barbie et al. identify TBK1 as a kinase in the NF-κB signalling pathway that is essential for the survival of KRAS-transformed cells. TBK1 induces anti-apoptotic signals and may be a therapeutic cancer target. And in an elegant mouse model for lung cancer driven by Kras mutation and loss of p53, Meylan et al. show that NF-κB signalling is activated by the concerted actions of these two alterations and required for tumour initiation and tumour maintenance.

Date: 2009
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DOI: 10.1038/nature08460

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