Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells
Author(s)
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; ... Show more Show less
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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.
Date issued
2009-05Department
Koch Institute for Integrative Cancer Research at MITJournal
Cell
Publisher
Elsevier B.V.
Citation
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.
Version: Final published version
ISSN
00928674
1097-4172