Targeting DNA Repair in Cancer: Beyond PARP Inhibitors.
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Date
2017-01Author
Brown, JS
O'Carrigan, B
Jackson, SP
Yap, TA
Type
Journal Article
Metadata
Show full item recordAbstract
Germline aberrations in critical DNA-repair and DNA damage-response (DDR) genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2-mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell-cycle checkpoint activation, trigger apoptosis, and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations.Significance Various inhibitors of DDR components are in preclinical and clinical development. A thorough understanding of DDR pathway complexities must now be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success. Cancer Discov; 7(1); 20-37. ©2016 AACR.
Collections
Subject
Animals
Humans
Neoplasms
Genetic Predisposition to Disease
Antineoplastic Agents
Drug Screening Assays, Antitumor
DNA Repair
Mutation
Poly(ADP-ribose) Polymerase Inhibitors
Research team
Medicine Drug Development Unit (de Bono)
Language
eng
Date accepted
2016-11-07
License start date
2017-01
Citation
Cancer discovery, 2017, 7 (1), pp. 20 - 37