Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1

Nature. 2009 Nov 5;462(7269):108-12. doi: 10.1038/nature08460. Epub 2009 Oct 21.

Abstract

The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IkappaB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-kappaB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-kappaB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Apoptosis
  • Cell Line, Tumor
  • Cell Survival
  • Gene Expression Profiling
  • Genes, Lethal
  • Genes, ras / genetics*
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Oncogene Protein p21(ras) / genetics*
  • Oncogene Protein p21(ras) / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-rel / metabolism
  • RNA Interference*
  • Signal Transduction
  • bcl-X Protein / metabolism

Substances

  • BCL2L1 protein, human
  • Proto-Oncogene Proteins c-rel
  • bcl-X Protein
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • Oncogene Protein p21(ras)

Associated data

  • GEO/GSE17643
  • GEO/GSE17671
  • GEO/GSE17672