Mar 18, 2017

PARP inhibitors: Synthetic lethality in the clinic

Science
Christopher J Lord, Alan Ashworth

Abstract

PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.

  • References66
  • Citations126
  • References66
  • Citations126

Citations

Mentioned in this Paper

BRCA2 Protein
BRCA1 protein, human
PARP1
Antineoplastic Agents
Germ-Line Mutation
Clinic
DNA Repair
Base Excision Repair
Neoplasms
PARP1 protein, human

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