Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response

Cancer Cell. 2014 Feb 10;25(2):243-56. doi: 10.1016/j.ccr.2014.01.005.

Abstract

Mutations in KRAS are prevalent in human cancers and universally predictive of resistance to anticancer therapeutics. Although it is widely accepted that acquisition of an activating mutation endows RAS genes with functional autonomy, recent studies suggest that the wild-type forms of Ras may contribute to mutant Ras-driven tumorigenesis. Here, we show that downregulation of wild-type H-Ras or N-Ras in mutant K-Ras cancer cells leads to hyperactivation of the Erk/p90RSK and PI3K/Akt pathways and, consequently, the phosphorylation of Chk1 at an inhibitory site, Ser 280. The resulting inhibition of ATR/Chk1 signaling abrogates the activation of the G2 DNA damage checkpoint and confers specific sensitization of mutant K-Ras cancer cells to DNA damage chemotherapeutic agents in vitro and in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Survival / drug effects
  • Cell Transformation, Neoplastic / pathology*
  • Checkpoint Kinase 1
  • DNA Damage / drug effects
  • DNA Damage / genetics*
  • Drug Resistance, Neoplasm
  • Female
  • Flow Cytometry
  • GTP Phosphohydrolases / antagonists & inhibitors
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mutation / genetics
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • ras Proteins / genetics*
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • KRAS protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 90-kDa
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • GTP Phosphohydrolases
  • NRAS protein, human
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins