Key Points
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DNA repair defects are targets for chemotherapy drugs.
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DNA damage response (DDR) genes are also targets for resistance mechanisms that are acquired during chemotherapy treatment.
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To enhance chemotherapy response, the DDR may be targeted by reactivation of p53, by inhibition of cell cycle checkpoints or by inhibition of DNA repair processes.
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Therapy resistance of homologous recombination (HR)-deficient tumours may be caused by genetic reversion of the HR defect, by residual HR activity, by rewiring of DNA repair pathways or by tumour heterogeneity.
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Robust biomarkers are required to maximize the effectiveness of therapy targeting HR deficiency.
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The best possible treatments might involve combinations of chemotherapy drugs and/or targeted therapeutics to eradicate tumours before resistant tumour cell clones arise.
Abstract
Tumours with specific DNA repair defects can be completely dependent on back-up DNA repair pathways for their survival. This dependence can be exploited therapeutically to induce synthetic lethality in tumour cells. For instance, homologous recombination (HR)-deficient tumours can be effectively targeted by DNA double-strand break-inducing agents. However, not all HR-defective tumours respond equally well to this type of therapy. Tumour cells may acquire resistance by invoking biochemical mechanisms that reduce drug action or by acquiring additional alterations in DNA damage response pathways. A thorough understanding of these processes is important for predicting treatment response and for the development of novel treatment strategies that prevent the emergence of therapy-resistant tumours.
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Acknowledgements
The authors are supported by grants from the Dutch Cancer Society, the Netherlands Organization of Scientific Research (NWO), the 7th framework programme of the European Union, and the Cancer Systems Biology Center (CSBC) funded by the NWO. We thank H. te Riele and S. Rottenberg for critically reading the Review, and M. van Vugt for helpful suggestions on figure 1.
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Supplementary information
Supplementary information S1
Overview of DDR proteins shown in Box 1 and their association with cancer (PDF 146 kb)
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Glossary
- Homologous recombination
-
(HR). A recombination reaction between two homologous DNA duplexes.
- Synthetic lethal
-
A lethal combination of individually non-lethal mutations in two or more genes.
- Mitotic catastrophe
-
An event in which a cell is destroyed during mitosis because of aberrant chromosome segregation or DNA damage.
- Focus
-
DNA damage response foci are transiently formed sites in the nucleus where DNA damage response proteins are concentrated and recruited to DNA lesions.
- Intrinsic resistance
-
Primary (pre-existing) resistance to cytotoxic treatment.
- Acquired resistance
-
Secondary resistance, which results from natural selection of tumour cell clones carrying (epi)genetic alterations that confer resistance to cytotoxic treatment.
- Caretaker genes
-
Tumour suppressor genes that are required for the maintenance of genome stability.
- Missense mutations
-
Gene mutations that lead to the alteration of a single amino acid in the encoded protein.
- Hotspot mutations
-
Frequently occurring, nonrandom mutations.
- DNA end resection
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The processing of DNA ends by nucleases to generate 3′ single-stranded DNA tails.
- Microsatellite instability
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Variation in the length of microsatellites (repeating DNA sequences of up to 6 nucleotides).
- Hypomorphic mutations
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Mutations that leave a gene partially functional.
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Bouwman, P., Jonkers, J. The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer 12, 587–598 (2012). https://doi.org/10.1038/nrc3342
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DOI: https://doi.org/10.1038/nrc3342
