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DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications

Nature Reviews Drug Discovery volume 24, pages 19–39 (2025)Cite this article

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Abstract

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.

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Fig. 1: _targeting the DDR response.
Fig. 2: Timeline of PARP inhibitor development and approvals.
Fig. 3: Comprehensive DDR inhibitor landscape per _target, development stage (preclinical or clinical) and status (active, not active or discontinued).

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Authors and Affiliations

  1. BC Cancer Vancouver Centre and Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Yvette Drew

  2. Research Unit Oncology, EMD Serono, Billerica, MA, USA

    Frank T Zenke

  3. Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    Nicola J Curtin

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All authors researched data for article, contributed substantially to discussion of content, wrote the article and edited and reviewed the manuscript before submission.

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Correspondence to Nicola J Curtin.

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Competing interests

Y.D. has participated in advisory boards for Clovis Oncology, AstraZeneca, Merck, Tesaro Inc (now GlaxoSmithKline), GlaxoSmithKline and Genmab. Y.D. has received research grant funding from Clovis Oncology and was involved in the preclinical and clinical development of rucaparib. Y.D. has received royalties for her involvement in the development of rucaparib. Y.D. has received research grant funding from AstraZeneca, Tesaro Inc and Roche. F.T.Z. was an employee at EMD Serono, Billerica, MA an affiliate of Merck KGaA, Darmstadt, Germany. Merck KGaA, Darmstadt, Germany, and/or its affiliates have certain rights in patents, patent applications pertaining to DNA Damage Response inhibitors, and F. Z. is named inventor on several patents. N.J.C. was involved in the development of rucaparib, receiving grant funding from Agouron Pharmaceuticals and Pfizer Oncology. She has received grant funding from BioMarin for translational studies with talazoparib. She was involved in the development of DNA-PK inhibitors and ATM inhibitors, receiving grant funding from Kudos (subsequently acquired by AstraZeneca). She was involved in the preclinical evaluation of ATR inhibitors, receiving grant funding from Vertex and Merck. She is inventor on several patents concerning PARP, DNA-PK, ATM and ATR inhibitors. She has received grant funding from Breakpoint Pharmaceuticals and has consulted for Abbvie and Tesaro on PARP inhibitors and Sierra Oncology on CHK1 inhibitors, she currently consults for Duke Street Bio. She diverts her royalty payments to charity.

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Related links

Beacon-Db: https://data.beacon-intelligence.com/

DepMap-ATR: https://depmap.org/portal/gene/ATR?tab=overview

DepMap-DNA-PK: https://depmap.org/portal/gene/PRKDC?tab=overview

DepMap-POLQ: https://depmap.org/portal/gene/POLQ?tab=overview

DepMap-USP1: https://depmap.org/portal/gene/USP1?tab=overview

DepMap-WEE1: https://depmap.org/portal/gene/WEE1?tab=overview

DepMap-WRN: https://depmap.org/portal/gene/WRN?tab=overview

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Drew, Y., Zenke, F.T. & Curtin, N.J. DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications. Nat Rev Drug Discov 24, 19–39 (2025). https://doi.org/10.1038/s41573-024-01060-w

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