Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies.
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Date
2018-07-13ICR Author
Author
Minchom, A
Aversa, C
Lopez, J
Type
Journal Article
Metadata
Show full item recordAbstract
Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit - for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.
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Research team
Medicine (de Bono Prostate)
Language
eng
Date accepted
2018-06-08
License start date
2018-01
Citation
Therapeutic advances in medical oncology, 2018, 10 pp. 1758835918786658 - ?
Publisher
SAGE PUBLICATIONS LTD