PARP inhibitors: Synthetic lethality in the clinic

CJ Lord, A Ashworth - Science, 2017 - science.org
CJ Lord, A Ashworth
Science, 2017science.org
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 …
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.
AAAS