Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells
Name
Scholl-2009-Synthetic Lethal Int.pdf
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2.25 MB
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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
Date Issued
May 2009
Journal
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
Abstract
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.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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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.
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DOI of Published Version
https://doi.org/10.1016/j.cell.2009.03.017
