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Accession IconGSE15151

Synthetic Lethal Interaction Between Oncogenic KRAS Dependency and Suppression of STK33 in Human Cancer Cells

Organism Icon Homo sapiens
Sample Icon 8 Downloadable Samples
Technology Badge Icon Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)

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Description
Many human oncogenes are challenging therapeutic targets. An alternative to direct 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 the broad spectrum of mutant KRAS-driven cancers, and demonstrate the potential of RNAi screens for discovering critical functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers associated with undruggable genetic alterations.
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