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Targeting DNA damage response pathways in cancer

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From Nature Reviews Cancer

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Abstract

Cells have evolved a complex network of biochemical pathways, collectively known as the DNA damage response (DDR), to prevent detrimental mutations from being passed on to their progeny. The DDR coordinates DNA repair with cell-cycle checkpoint activation and other global cellular responses. Genes encoding DDR factors are frequently mutated in cancer, causing genomic instability, an intrinsic feature of many tumours that underlies their ability to grow, metastasize and respond to treatments that inflict DNA damage (such as radiotherapy). One instance where we have greater insight into how genetic DDR abrogation impacts on therapy responses is in tumours with mutated BRCA1 or BRCA2. Due to compromised homologous recombination DNA repair, these tumours rely on alternative repair mechanisms and are susceptible to chemical inhibitors of poly(ADP-ribose) polymerase (PARP), which specifically kill homologous recombination-deficient cancer cells, and have become a paradigm for targeted cancer therapy. It is now clear that many other synthetic-lethal relationships exist between DDR genes. Crucially, some of these interactions could be exploited in the clinic to target tumours that become resistant to PARP inhibition. In this Review, we discuss state-of-the-art strategies for DDR inactivation using small-molecule inhibitors and highlight those compounds currently being evaluated in the clinic.

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Fig. 1: Cell cycle-dependent DDR activation at DSBs.
Fig. 2: Major and backup pathways of DSB repair.

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Acknowledgements

The laboratories of the authors are supported by the University of Oxford and a Cancer Research UK Programme Award (DRCPGM\100001) to M.T. and a Cancer Research UK Career Development Fellowship (C29215/A20772) to A.N.B.

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Authors and Affiliations

  1. Genome Stability and Tumourigenesis Group, Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK

    Florian J. Groelly, Rebecca A. Dagg & Madalena Tarsounas

  2. Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

    Matthew Fawkes & Andrew N. Blackford

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  1. Florian J. Groelly
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Contributions

All authors researched data for the article and contributed substantially to discussion of the content. F.J.G., A.N.B. and M.T. wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Andrew N. Blackford or Madalena Tarsounas.

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Glossary

cGAS–STING axis

A pathway that detects cytosolic DNA and activates innate immune responses.

Chromothripsis

The process of chromosome shattering followed by incorrect repair.

Displacement loop

(D-loop). A DNA structure formed when a double helix is separated by invasion of a complementary single-stranded DNA end during homologous recombination.

Double Holliday junction

A four-way joint DNA molecule and homologous recombination intermediate that can form after second-end capture and ligation.

Micronuclei

Cytosolic structures containing a chromosome or chromosome fragment that are not incorporated in the nucleus during mitosis.

One-ended DSBs

Double-stranded DNA ends formed when a replication fork collapses, where there is no second DNA end available for ligation.

Second-end capture

The annealing step that pairs the second resected single-stranded DNA end from one side of a double-strand break with the joint molecule formed by invasion of a template DNA by the first resected DNA end during homologous recombination.

Shieldin complex

A protein complex consisting of SHLD1–SHLD2–SHLD3, which acts together with 53BP1–RIF1–REV7 to limit end resection at DNA double-strand breaks.

Two-ended DSBs

DNA double-strand breaks (DSBs) where both ends are available for ligation.

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Groelly, F.J., Fawkes, M., Dagg, R.A. et al. Targeting DNA damage response pathways in cancer. Nat Rev Cancer 23, 78–94 (2023). https://doi.org/10.1038/s41568-022-00535-5

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