PARP Inhibitors: The First Synthetic Lethal Targeted Therapy

By C. Lord, Alan Ashworth. Science, 2017

2,440 citations recorded by the source corpus.

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.

Subfields: Electrical and Electronic Engineering, Oncology

View Paper: https://www.semanticscholar.org/paper/28d96db1f09a484afd03fdae6843b5f4c80769be

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In Oncology

Citations in the corpus

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas (2018, positive): “…cancer cells to alkylating chemotherapy agents (Soll et al., 2017; Weller et al., 2015); and BRCA mutant, HR-deﬁcient breast and ovarian cancers, which are sensitive to inhibition of PARP1 , a central protein in the BER pathway (Bryant et al., 2005; Farmer et al., 2005; Lord and Ashworth, 2017).”
ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. (2017, background): “, 2005), it is notable that growing evidence highlights how loss of ATM and other DDR factors also leads to PARP-inhibitor sensitivity in cancers (Lord and Ashworth, 2017).”