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 rem...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2014
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| Online Access: | http://hdl.handle.net/1721.1/84607 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-1446-7256 |
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| author | Sandy, Peter Meylan, Etienne Reiling, Jan H. Hoersch, Sebastian Barbie, David A. Tamayo, Pablo Boehm, Jesse S. Kim, So Young Moody, Susan E. Dunn, Ian F. Schinzel, Anna C. Scholl, Claudia Frohling, Stefan Chan, Edmond M. Sos, Martin L. Michel, Kathrin Mermel, Craig H. Sabatini, David Lander, Eric Steven Jacks, Tyler E |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Sandy, Peter Meylan, Etienne Reiling, Jan H. Hoersch, Sebastian Barbie, David A. Tamayo, Pablo Boehm, Jesse S. Kim, So Young Moody, Susan E. Dunn, Ian F. Schinzel, Anna C. Scholl, Claudia Frohling, Stefan Chan, Edmond M. Sos, Martin L. Michel, Kathrin Mermel, Craig H. Sabatini, David Lander, Eric Steven Jacks, Tyler E |
| author_sort | Sandy, Peter |
| collection | MIT |
| description | 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 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. |
| first_indexed | 2024-09-23T12:34:53Z |
| format | Article |
| id | mit-1721.1/84607 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:34:53Z |
| publishDate | 2014 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/846072022-10-01T09:52:07Z Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 Sandy, Peter Meylan, Etienne Reiling, Jan H. Hoersch, Sebastian Barbie, David A. Tamayo, Pablo Boehm, Jesse S. Kim, So Young Moody, Susan E. Dunn, Ian F. Schinzel, Anna C. Scholl, Claudia Frohling, Stefan Chan, Edmond M. Sos, Martin L. Michel, Kathrin Mermel, Craig H. Sabatini, David Lander, Eric Steven Jacks, Tyler E Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Sandy, Peter Meylan, Etienne Reiling, Jan H. Hoersch, Sebastian Sabatini, David M. Lander, Eric S. Jacks, Tyler E. 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 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. 2014-01-27T20:47:52Z 2014-01-27T20:47:52Z 2009-10 2009-01 Article http://purl.org/eprint/type/JournalArticle 0028-0836 1476-4687 http://hdl.handle.net/1721.1/84607 Barbie, David A., Pablo Tamayo, Jesse S. Boehm, So Young Kim, Susan E. Moody, Ian F. Dunn, Anna C. Schinzel, et al. “Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.” Nature 462, no. 7269 (October 21, 2009): 108-112. https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1038/nature08460 Nature Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Sandy, Peter Meylan, Etienne Reiling, Jan H. Hoersch, Sebastian Barbie, David A. Tamayo, Pablo Boehm, Jesse S. Kim, So Young Moody, Susan E. Dunn, Ian F. Schinzel, Anna C. Scholl, Claudia Frohling, Stefan Chan, Edmond M. Sos, Martin L. Michel, Kathrin Mermel, Craig H. Sabatini, David Lander, Eric Steven Jacks, Tyler E Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 |
| title | Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 |
| title_full | Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 |
| title_fullStr | Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 |
| title_full_unstemmed | Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 |
| title_short | Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 |
| title_sort | systematic rna interference reveals that oncogenic kras driven cancers require tbk1 |
| url | http://hdl.handle.net/1721.1/84607 https://orcid.org/0000-0001-5785-8911 https://orcid.org/0000-0002-1446-7256 |
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