Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations

Cell Cycle. 2011 Apr 15;10(8):1192-9. doi: 10.4161/cc.10.8.15273. Epub 2011 Apr 15.


Utilizing the concept of synthetic lethality has provided new opportunities for the development of targeted therapies, by allowing the targeting of loss of function genetic aberrations. In cancer cells with BRCA1 or BRCA2 loss of function, which harbor deficiency of DNA repair by homologous recombination, inhibition of PARP1 enzymatic activity leads to an accumulation of single strand breaks that are converted to double strand breaks but cannot be repaired by homologous recombination. Inhibition of PARP has therefore been advanced as a novel targeted therapy for cancers harboring BRCA1/2 mutations. Preclinical and preliminary clinical evidence, however, suggests a potentially broader scope for PARP inhibitors. Loss of function of various proteins involved in double strand break repair other than BRCA1/2 has been suggested to be synthetically lethal with PARP inhibition. Inactivation of these genes has been reported in a subset of human cancers and might therefore constitute predictive biomarkers for PARP inhibition. Here we discuss the evidence that the clinical use of PARP inhibition may be broader than targeting of cancers in BRCA1/2 germ-line mutation carriers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / genetics
  • BRCA2 Protein / deficiency*
  • BRCA2 Protein / genetics
  • Clinical Trials as Topic
  • DNA Methylation / drug effects
  • DNA Repair / drug effects*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Epistasis, Genetic
  • Female
  • Gene Expression
  • Germ-Line Mutation
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Targeted Therapy / methods
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Recombination, Genetic* / drug effects


  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA2 Protein
  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases