Oncogenic K-ras "addiction" and synthetic lethality

Cell Cycle. 2009 Sep 1;8(17):2676-7. doi: 10.4161/cc.8.17.9336. Epub 2009 Sep 23.

Abstract

Mutational activation of the K-ras gene is a frequent oncogenic event in human cancers, associated with poor clinical prognosis and resistance to treatment. Despite efforts to develop therapeutics that target K-ras or its downstream effector molecules, clinical benefit in this setting has not yet been achieved. An alternative approach to K-ras mutant cancers involves the identification of genes that selectively drive the maintenance of tumors that are “addicted” to or dependent on mutant K-ras. Disruption of these genes would result in “synthetic lethality” specifically in cancer cells driven by mutant K-ras, thereby potentially sparing non-tumor cells. Through this approach, three recent reports have identified PLK1, STK33, SYK, RON and integrin β6 as previously unappreciated pharmacologically tractable targets in the setting of K-ras activation, which drive growth and survival selectively in K-ras-dependent cancer cells.

Publication types

  • Editorial

MeSH terms

  • Apoptosis
  • Cell Cycle Proteins / metabolism
  • Genes, ras*
  • Humans
  • Integrin beta Chains / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mutation
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • RNA Interference
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Syk Kinase

Substances

  • Cell Cycle Proteins
  • Integrin beta Chains
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • integrin beta6
  • Protein-Tyrosine Kinases
  • RON protein
  • Receptor Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Protein-Serine-Threonine Kinases
  • STK33 protein, human
  • polo-like kinase 1
  • Proto-Oncogene Proteins p21(ras)