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Science. 2017 Mar 17;355(6330):1152-1158. doi: 10.1126/science.aam7344. Epub 2017 Mar 16.

PARP inhibitors: Synthetic lethality in the clinic.

Author information

1
The Cancer Research UK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. chris.lord@icr.ac.uk alan.ashworth@ucsf.edu.
2
University of California, San Francisco (UCSF), Helen Diller Family Comprehensive Cancer Center, 1450 Third Street, San Francisco, CA 94158, USA. chris.lord@icr.ac.uk alan.ashworth@ucsf.edu.

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.

PMID:
28302823
PMCID:
PMC6175050
DOI:
10.1126/science.aam7344
[Indexed for MEDLINE]
Free PMC Article

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