Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells
An alternative to therapeutic targeting of oncogenes is to perform “synthetic lethality” screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier B.V.
2015
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| Online Access: | http://hdl.handle.net/1721.1/96267 https://orcid.org/0000-0001-5785-8911 |
| _version_ | 1811075429227823104 |
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| author | Scholl, Claudia Frohling, Stefan Dunn, Ian F. Schinzel, Anna C. Barbie, David A. Kim, So Young Silver, Serena J. Tamayo, Pablo Wadlow, Raymond C. Ramaswamy, Sridhar Dohner, Konstanze Bullinger, Lars Sandy, Peter Boehm, Jesse S. Root, David E. Hahn, William C. Gilliland, D. Gary Jacks, Tyler E |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Scholl, Claudia Frohling, Stefan Dunn, Ian F. Schinzel, Anna C. Barbie, David A. Kim, So Young Silver, Serena J. Tamayo, Pablo Wadlow, Raymond C. Ramaswamy, Sridhar Dohner, Konstanze Bullinger, Lars Sandy, Peter Boehm, Jesse S. Root, David E. Hahn, William C. Gilliland, D. Gary Jacks, Tyler E |
| author_sort | Scholl, Claudia |
| collection | MIT |
| description | An alternative to therapeutic targeting of oncogenes is to perform “synthetic lethality” screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with “undruggable” genetic alterations. |
| first_indexed | 2024-09-23T10:05:44Z |
| format | Article |
| id | mit-1721.1/96267 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:05:44Z |
| publishDate | 2015 |
| publisher | Elsevier B.V. |
| record_format | dspace |
| spelling | mit-1721.1/962672022-09-30T18:52:48Z Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells Scholl, Claudia Frohling, Stefan Dunn, Ian F. Schinzel, Anna C. Barbie, David A. Kim, So Young Silver, Serena J. Tamayo, Pablo Wadlow, Raymond C. Ramaswamy, Sridhar Dohner, Konstanze Bullinger, Lars Sandy, Peter Boehm, Jesse S. Root, David E. Hahn, William C. Gilliland, D. Gary Jacks, Tyler E Koch Institute for Integrative Cancer Research at MIT Sandy, Peter Jacks, Tyler E. An alternative to therapeutic targeting of oncogenes is to perform “synthetic lethality” screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with “undruggable” genetic alterations. National Institutes of Health (U.S.) (grant R33 CA128625) National Institutes of Health (U.S.) (grant NIH U54 CA112962) National Institutes of Health (U.S.) (grant P01 CA095616) National Institutes of Health (U.S.) (grant P01 CA66996) Starr Cancer Consortium Doris Duke Charitable Foundation MPN Research Foundation Deutsche Forschungsgemeinschaft (grant SCHO 1215/1-1) Deutsche Forschungsgemeinschaft (grant FR 2113/1-1) Brain Science Foundation Leukemia & Lymphoma Society of America 2015-03-30T20:14:32Z 2015-03-30T20:14:32Z 2009-05 2009-01 Article http://purl.org/eprint/type/JournalArticle 00928674 1097-4172 http://hdl.handle.net/1721.1/96267 Scholl, Claudia, Stefan Fröhling, Ian F. Dunn, Anna C. Schinzel, David A. Barbie, So Young Kim, Serena J. Silver, et al. “Synthetic Lethal Interaction Between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells.” Cell 137, no. 5 (May 2009): 821–834. © 2009 Elsevier Inc. https://orcid.org/0000-0001-5785-8911 en_US http://dx.doi.org/10.1016/j.cell.2009.03.017 Cell Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier B.V. Elsevier |
| spellingShingle | Scholl, Claudia Frohling, Stefan Dunn, Ian F. Schinzel, Anna C. Barbie, David A. Kim, So Young Silver, Serena J. Tamayo, Pablo Wadlow, Raymond C. Ramaswamy, Sridhar Dohner, Konstanze Bullinger, Lars Sandy, Peter Boehm, Jesse S. Root, David E. Hahn, William C. Gilliland, D. Gary Jacks, Tyler E Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells |
| title | Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells |
| title_full | Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells |
| title_fullStr | Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells |
| title_full_unstemmed | Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells |
| title_short | Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells |
| title_sort | synthetic lethal interaction between oncogenic kras dependency and stk33 suppression in human cancer cells |
| url | http://hdl.handle.net/1721.1/96267 https://orcid.org/0000-0001-5785-8911 |
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