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  • Review Article
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DNA repair dysregulation from cancer driver to therapeutic target

Nature Reviews Cancer volume 12, pages 801–817 (2012)Cite this article

Subjects

Key Points

  • The DNA damage response (DDR) coordinates the repair of DNA and the activation of cell cycle checkpoints to arrest the cell to allow time for repair.

  • DNA is subject to a high level of endogenous damage and the DDR is essential for the maintenance of genomic stability and survival.

  • Dysregulation of the DDR can lead to genomic instability that promotes cancer development but that is exploitable with both conventional cytotoxic therapy and DDR inhibitors. Downregulated DDR pathways render the tumour sensitive to specific cytotoxics and some DDR inhibitors. Upregulated DDR pathways confer therapeutic resistance.

  • Inhibitors of the DDR have been developed to overcome resistance and to augment the activity of conventional therapy.

  • Loss of a DDR pathway can lead to dependence on a compensatory pathway, and targeting this second pathway may render endogenous DNA damage cytotoxic by a process termed synthetic lethality, which will be tumour-specific because the normal tissues in the animal (or person) will have functional DNA repair.

  • Despite promising preclinical data combining DDR inhibitors with conventional cytotoxic agents, these combinations have been less successful in the clinic and are often associated with toxicity. Exploitation of DDR defects by synthetic lethality is a more promising approach. Clinical data on the use of poly(ADP-ribose) polymerase (PARP) inhibitors in homologous recombination repair (HRR)-defective tumours are encouraging.

  • Robust and validated biomarkers to identify DDR defects that are exploitable by both conventional cytotoxic therapy and agents targeting the DDR are needed to effectively stratify patients.

Abstract

Dysregulation of DNA damage repair and signalling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. Dysfunction of one DNA repair pathway may be compensated for by the function of another compensatory DDR pathway, which may be increased and contribute to resistance to DNA-damaging chemotherapy and radiotherapy. Therefore, DDR pathways make an ideal target for therapeutic intervention; first, to prevent or reverse therapy resistance; and second, using a synthetic lethal approach to specifically kill cancer cells that are dependent on a compensatory DNA repair pathway for survival in the context of cancer-associated oxidative and replicative stress. These hypotheses are currently being tested in the laboratory and are being translated into clinical studies

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Figure 1: Sources of DNA damage and their repair.
Figure 2: Base excision repair.
Figure 3: Nucleotide excision repair.
Figure 4: Mismatch repair.
Figure 5: DNA double-strand break and interstrand crosslink repair.
Figure 6: Signalling DNA damage to cell cycle checkpoints.
Figure 7: Synthetic lethality.

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Acknowledgements

The author would like to thank her laboratory group and colleagues for their help and support and CR UK, Agouron (then Pfizer, then Clovis), KuDOS, AstraZeneca, EPSRC and MRC for supporting her research. Special thanks go to Z. Hostomsky, who was her PARP champion at Agouron and Pfizer.

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  1. Newcastle University, Northern Institute for Cancer Research, Newcastle upon Tyne, NE2 4HH, UK

    Nicola J. Curtin

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Competing interests

N.J.C. is a named inventor on PARP inhibitor and DNA-PK inhibitor patents. N.J.C. is currently or previously in receipt of research funding from Agouron Pharmaceuticals, BioMarin, BiPAR and Pfizer for PARP-related studies and from AstraZeneca and KuDOS for DNA-PK and ATM-related studies and from Vertex for ATR-related studies. N.J.C. has received honoraria for speaking at AACR, ASCO, Abbott and Consultancy funding from BioMarin and Eisai.

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Glossary

Cell cycle checkpoints

Points in the cell division cycle at which the cell may arrest in response to stress; for example, following DNA damage to prevent damage becoming inherited by daughter cells. The G1 checkpoint controls entry into S phase, the S phase checkpoint halts the progression of S phase and the G2 checkpoint controls entry into mitosis.

Replication stress

The harmful effect of partially replicated DNA. It can be caused by oncogene-induced hyper-replication that activates origins more than once per S phase, by nucleotide pool imbalance or by DNA damage; for example, by reactive oxygen species.

Synthetic lethality

Cell death caused by inactivation (mutation or inhibition) of two genes or their products or two pathways, when inactivation of either alone is not lethal.

Alkylations

Transfers of an alkyl group from one molecule to another; for example, the transfer of a methyl group from temozolomide to guanine.

Myelosuppression

Impairment of bone marrow function resulting in reduced numbers of blood cells (red or white) or platelets.

Phase III trials

Test the efficacy of the novel drug, or combination, and side effects compared with the standard-of-care for that tumour type, with patients randomized to two groups. Numbers of patients are larger (1,000–3,000) than other Phase trials.

Phase II trials

Use the maximum tolerated dose to treat groups of patients with a particular tumour type, these studies determine whether the drug, or drug combination, is effective in one or more tumour types and are used to further monitor drug safety. These generally involve small numbers of patients (100–300).

Deamination

Removal of an amide group; for example, deamination of adenosine to inosine (adenine to hypoxanthine).

Oxidative phosphorylation

Metabolic pathway for the generation of ATP occurring in the mitochondria of eukaryotes in which NADH and succinate from the Krebs' cycle are oxidized by the electron transport chain. The process also generates reactive oxygen species.

Abasic sites

(Also known as apurinic or apyrimidinic (AP) sites). A site on the DNA where there is no purine or pyrimidine base.

Antimetabolites

Substances that resemble a normal precursor or cofactor, usually for DNA synthesis, which interfere with the normal metabolic process; for example, nucleoside analogues such as 6-thioguanine or folate analogues such as pemetrexed.

Phase I trial

Determines pharmacokinetics (absorption, distribution, metabolism and excretion (ADME)) and the safe dose or maximum tolerated dose of a novel agent or combination. They are conducted in 20–80 patients with a variety of tumour types who have often undergone treatment with standard-of-care but for whom no effective therapy options are available. These studies usually involve escalating the dose of the novel agent in successive cohorts of patients until unacceptable toxicities are seen.

Microsatellite instability

(MSI). Microsatellites are sequences in DNA; for example, ten thymidines in direct sequence. MSI occurs when this sequence is shortened or lengthened owing to defects in the mismatch repair system.

Radiomimetics

Drugs that introduce the same DNA damage as ionizing radiation.

Fanconi anaemia

A rare genetic disorder that results in aplastic anaemia, leukaemia and cancer susceptibility, and hypersensitivity to DNA crosslinking agents. The pathway is responsible for the repair of DNA interstrand crosslinks and overlaps somewhat with homologous recombination repair.

Crosslinking agents

Molecules with two reactive groups (for example, bifunctional alkylating agents and cisplatin) that can react with two groups in DNA on the same strand to form intrastrand crosslinks or opposite strands to form interstrand crosslinks.

Focus

The accumulation of a substance (usually protein) that may be identified and visualized (usually by a fluorescently tagged antibody) in one spot.

Pharmacodynamic

The physiological or biochemical effect of a drug on the body. A pharmacodynamic biomarker is a measure of this effect; for example, the product of an enzyme reaction may be reduced by a drug that inhibits the enzyme.

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Curtin, N. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12, 801–817 (2012). https://doi.org/10.1038/nrc3399

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