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PARP inhibitors: Synthetic lethality in the clinic.

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Date
2017-03-16
ICR Author
Lord, Christopher
Author
Lord, CJ
Ashworth, A
Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/543
DOI
https://doi.org/10.1126/science.aam7344
Collections
  • Breast Cancer Research
  • Molecular Pathology
Subject
Humans
Neoplasms
DNA Damage
Ubiquitin-Protein Ligases
BRCA2 Protein
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Antineoplastic Protocols
DNA Repair
Germ-Line Mutation
Clinical Trials as Topic
Poly(ADP-ribose) Polymerase Inhibitors
Synthetic Lethal Mutations
Research team
Gene Function
Language
eng
Date accepted
2016-02-17
License start date
2017-03-16
Citation
Science (New York, N.Y.), 2017, 355 (6330), pp. 1152 - 1158

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