Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Scholl, C; Fröhling, S; Dunn, IF; Schinzel, AC; Barbie, DA; Kim, SY; Silver, SJ; Tamayo, P; Wadlow, RC; Ramaswamy, S; Döhner, K; Bullinger, L; Sandy, P; Boehm, JS; Root, DE; Jacks, T; Hahn, WC; Gilliland, DG

Published Date

  • May 29, 2009

Published In

Volume / Issue

  • 137 / 5

Start / End Page

  • 821 - 834

PubMed ID

  • 19490892

Pubmed Central ID

  • 19490892

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2009.03.017

Language

  • eng

Conference Location

  • United States