Mechanisms of resistance to therapies targeting BRCA-mutant cancers

Nat Med. 2013 Nov;19(11):1381-8. doi: 10.1038/nm.3369. Epub 2013 Oct 7.


Synthetic lethality provides a potential mechanistic framework for the therapeutic targeting of genetic and functional deficiencies in cancers and is now being explored widely. The first clinical exemplification of synthetic lethality in cancer has been the exploitation of inhibitors of poly-(ADP-ribose) polymerase (PARP) for the treatment of cancers with defects in the BRCA1 or BRCA2 tumor suppressor proteins, which are involved in the repair of DNA damage. Although this approach has shown promise, multiple potential resistance mechanisms have been identified. In this Perspective, we discuss these mechanisms and their relevance to the development of selective therapies for BRCA-deficient cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Chromosomal Proteins, Non-Histone / deficiency
  • Chromosomal Proteins, Non-Histone / genetics
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Drug Resistance, Neoplasm / genetics
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Genes, BRCA1*
  • Genes, BRCA2*
  • Humans
  • Mice
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Platinum Compounds / therapeutic use
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / genetics
  • Synthetic Biology
  • Translational Medical Research
  • Tumor Suppressor p53-Binding Protein 1


  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Platinum Compounds
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1
  • Poly(ADP-ribose) Polymerases