Synthetic lethality and cancer therapy: lessons learned from the development of PARP inhibitors

Annu Rev Med. 2015;66:455-70. doi: 10.1146/annurev-med-050913-022545. Epub 2014 Oct 17.

Abstract

The genetic concept of synthetic lethality, in which the combination or synthesis of mutations in multiple genes results in cell death, provides a framework to design novel therapeutic approaches to cancer. Already there are promising indications, from clinical trials exploiting this concept by using poly(ADP-ribose) polymerase (PARP) inhibitors in patients with germline BRCA1 or BRCA2 gene mutations, that this approach could be beneficial. We discuss the biological rationale for BRCA-PARP synthetic lethality, how the synthetic lethal approach is being assessed in the clinic, and how mechanisms of resistance are starting to be dissected. Applying the synthetic lethal concept to target non-BRCA-mutant cancers also has clear potential, and we discuss how some of the principles learned in developing PARP inhibitors might also drive the development of additional genetic approaches.

Keywords: BRCA1; BRCA2; breast cancer; drug resistance; ovarian cancer.

Publication types

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

MeSH terms

  • Benzamides / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Humans
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms, Cystic, Mucinous, and Serous / drug therapy*
  • Neoplasms, Cystic, Mucinous, and Serous / genetics
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Phthalazines / therapeutic use
  • Piperazines / therapeutic use
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*

Substances

  • Benzamides
  • Enzyme Inhibitors
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • iniparib
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • olaparib