A Genome-Wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions With the Ras Oncogene

Cell. 2009 May 29;137(5):835-48. doi: 10.1016/j.cell.2009.05.006.

Abstract

Oncogenic mutations in the small GTPase Ras are highly prevalent in cancer, but an understanding of the vulnerabilities of these cancers is lacking. We undertook a genome-wide RNAi screen to identify synthetic lethal interactions with the KRAS oncogene. We discovered a diverse set of proteins whose depletion selectively impaired the viability of Ras mutant cells. Among these we observed a strong enrichment for genes with mitotic functions. We describe a pathway involving the mitotic kinase PLK1, the anaphase-promoting complex/cyclosome, and the proteasome that, when inhibited, results in prometaphase accumulation and the subsequent death of Ras mutant cells. Gene expression analysis indicates that reduced expression of genes in this pathway correlates with increased survival of patients bearing tumors with a Ras transcriptional signature. Our results suggest a previously underappreciated role for Ras in mitotic progression and demonstrate a pharmacologically tractable pathway for the potential treatment of cancers harboring Ras mutations.

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

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Colonic Neoplasms / metabolism*
  • Female
  • Genome, Human
  • Humans
  • Mice
  • Mice, Nude
  • Mitosis*
  • Mutation
  • Neoplasm Transplantation
  • Proteasome Inhibitors
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins p21(ras)
  • RNA Interference
  • Signal Transduction
  • Transplantation, Heterologous
  • ras Proteins / genetics*
  • ras Proteins / metabolism*

Substances

  • Cell Cycle Proteins
  • KRAS protein, human
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins