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Lookup NU author(s): Emerita Professor Nicola Curtin
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© Springer Nature Limited 2024.The DNA damage response (DDR) is a network of proteins that coordinate DNA repair and cell-cycle checkpoints to prevent damage being transmitted to daughter cells. DDR defects lead to genomic instability, which enables tumour development, but they also create vulnerabilities that can be used for cancer therapy. Historically, this vulnerability has been taken advantage of using DNA-damaging cytotoxic drugs and radiotherapy, which are more toxic to tumour cells than to normal tissues. However, the discovery of the unique sensitivity of tumours defective in the homologous recombination DNA repair pathway to PARP inhibition led to the approval of six PARP inhibitors worldwide and to a focus on making use of DDR defects through the development of other DDR-targeting drugs. Here, we analyse the lessons learnt from PARP inhibitor development and how these may be applied to new targets to maximize success. We explore why, despite so much research, no other DDR inhibitor class has been approved, and only a handful have advanced to later-stage clinical trials. We discuss why more reliable predictive biomarkers are needed, explore study design from past and current trials, and suggest alternative models for monotherapy and combination studies. Targeting multiple DDR pathways simultaneously and potential combinations with anti-angiogenic agents or immune checkpoint inhibitors are also discussed.
Author(s): Drew Y, Zenke FT, Curtin NJ
Publication type: Review
Publication status: Published
Journal: Nature Reviews Drug Discovery
Year: 2024
Pages: epub ahead of print
Online publication date: 12/11/2024
Acceptance date: 17/09/2024
ISSN (print): 1474-1776
ISSN (electronic): 1474-1784
Publisher: Nature Research
URL: https://doi.org/10.1038/s41573-024-01060-w
DOI: 10.1038/s41573-024-01060-w
