Targeting DNA Repair in Cancer: Beyond PARP Inhibitors
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Publication Date
2017-01-01Journal Title
Cancer Discovery
ISSN
2159-8274
Publisher
American Association for Cancer Research Inc.
Volume
7
Issue
1
Pages
20-37
Language
English
Type
Article
This Version
AM
Metadata
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Brown, J., O'Carrigan, B., Jackson, S., & Yap, T. (2017). Targeting DNA Repair in Cancer: Beyond PARP Inhibitors. Cancer Discovery, 7 (1), 20-37. https://doi.org/10.1158/2159-8290.CD-16-0860
Abstract
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.
$\textbf{SIGNIFICANCE}$: 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
Sponsorship
J.S. Brown, B. O'Carrigan, and T.A. Yap acknowledge support from the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). Research in The Jackson laboratory is funded by Cancer Research UK (CRUK) program grant number C6/A18796. Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P. Jackson receives his salary from the University of Cambridge, UK, supplemented by CRUK.
Funder references
Cancer Research UK (A18796)
Wellcome Trust (092096/Z/10/Z)
Cancer Research UK (A14492)
Identifiers
External DOI: https://doi.org/10.1158/2159-8290.CD-16-0860
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262245
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