DNA repair pathways as targets for cancer therapy

Key Points

  • Several cancer chemotherapy drugs work by producing excessive DNA damage that causes cell death directly or following DNA replication. Survival is promoted through repair of these lesions by a number of DNA repair pathways.

  • The efficacy of anticancer drugs is highly influenced by cellular DNA repair capacity. Inhibitors of DNA repair increase the efficacy of DNA-damaging anticancer drugs in preclinical models. Small-molecule inhibitors of DNA repair have been combined with conventional chemotherapy drugs in several phase I–II clinical trials.

  • Tumour development can be associated with perturbed DNA damage response and repair pathways. This perturbation results in reduced DNA repair capacity and increased genetic instability in tumour cells. Defects in one DNA repair pathway can be compensated for by other pathways. Such compensating pathways can be identified in synthetic lethality screens and then specifically targeted for treatment of DNA repair-defective tumours.

  • Evidence indicates that inhibitors of DNA repair pathways can work as single agents for the targeted treatment of DNA repair-defective cancers. This hypothesis is currently being tested in phase II trials in which patients with breast or ovarian cancers that are defective in homologous recombination are being treated with a poly(ADP-ribose) polymerase inhibitor.

  • Tumours often exhibit replication stress as a consequence of oncogene-induced growth signals or hypoxia-induced replication arrest. We propose that DNA repair inhibitors could be used to prevent the repair of replication lesions present in tumour cells and convert them into fatal replication lesions that specifically kill cancer cells.

Abstract

DNA repair pathways can enable tumour cells to survive DNA damage that is induced by chemotherapeutic treatments; therefore, inhibitors of specific DNA repair pathways might prove efficacious when used in combination with DNA-damaging chemotherapeutic drugs. In addition, alterations in DNA repair pathways that arise during tumour development can make some cancer cells reliant on a reduced set of DNA repair pathways for survival. There is evidence that drugs that inhibit one of these pathways in such tumours could prove useful as single-agent therapies, with the potential advantage that this approach could be selective for tumour cells and have fewer side effects.

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Figure 1: Overview of DNA repair pathways involved in repairing toxic DNA lesions formed by cancer treatments.
Figure 2: Synthetic lethal interactions to identify molecular targets for inhibitors of DNA repair.

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Acknowledgements

We would like to thank the Medical Research Council, The Swedish Research Council, The Swedish Cancer Society, The Swedish Children's Cancer Foundation, The Swedish Pain Relief Foundation and Cancer Research UK for financial support. We recognize that we were unable to cover all aspects of DNA repair in cancer in this Review. We apologize to those whom we have been unable to cite owing to space constraints.

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Correspondence to Thomas Helleday.

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Patents regarding targeting DNA repair have been filed by the University of Sheffield's and University of Oxford's technology transfer companies with Thomas Helleday as named inventor.

Supplementary information

Supplementary information S1 (Table)

Synthetic lethal interactions of S. cerevisiae genes that are homologous to human DNA repair and checkpoint genes implicated in cancer. (PDF 710 kb)

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DATABASES

ClinicalTrials.gov

NCT00475917

NCT00526617

National Cancer Institute

breast cancer

ovarian cancer

National Cancer Institute Drug Dictionary

5-fluorouracil

6-thioguanine

bleomycin

carboplatin

chlorambucil

cisplatin

cyclophosphamide

dacarbazine

decitabine

etoposide

gemcitabine

hydroxyurea

melphalan

mitomycin C

oxaliplatin

temozolomide

UCN-01

XL844

FURTHER INFORMATION

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Decitabine and Carboplatin in Relapsed Ovarian Cancer

Glossary

Alkylating agents

Electrophilic compounds that are reactive either directly or following metabolism and bind covalently to electron-rich atoms in DNA bases (that is, oxygen and nitrogen).

Antimetabolites

Compounds with similar chemical structures to nucleotide metabolites that interfere with nucleotide biosynthesis or are incorporated into DNA.

Non-homologous end joining

Connection and resealing of the two ends of a DNA double-strand break without the need for sequence homology between the ends.

Homologous recombination

A process that can copy a DNA sequence from an intact DNA molecule (often the newly synthesized sister chromatid) to repair or bypass replication lesions.

Base-excision repair

A repair pathway that replaces missing or modified DNA bases, such as those produced by alkylating agents or in spontaneously degraded DNA, with the correct DNA base.

Nucleotide-excision repair

A process that removes large DNA adducts or base modifications that distort the double helix and uses the opposite strand as template for repair.

Alkyltransferases

A class of enzymes that directly reverse DNA base modifications that are induced by alkylating agents by transferring the alkyl group from the base onto the protein.

DNA dioxygenases

A class of enzymes that directly reverse DNA base methylations through an oxidation mechanism. The human DNA dioxygenase ABH2 is thought to act at replication forks.

Mismatch repair

A process that acts during DNA replication to correct base-pairing errors made by the DNA polymerases.

Translesion synthesis

A mechanism during DNA replication in which the standard DNA polymerase is temporarily exchanged for a specialized polymerase that can synthesize DNA across base damage on the template strand.

Fanconi anaemia repair pathway

Proteins of this pathway, including BRCA2, are mutated in the hereditary disorder Fanconi anaemia (FA), resulting in hypersensitivity to inter-strand crosslinks. Evidence suggests that the FA pathway promotes the repair of stalled replication forks, possibly by activating HR and facilitating ATR- and ATM-dependent checkpoint signalling.

Endonuclease-mediated repair

A repair pathway that introduces a DNA single-strand break in a DNA structure to facilitate continuous repair.

RecQ-mediated repair

A repair pathway that unwinds complex DNA structure to facilitate repair.

Therapeutic index

The therapeutic index describes the ability of a treatment strategy to kill cancer cells in preference to cells in normal tissues.

Synthetic lethality

A genetic phenomenon in which the combination of two otherwise non-lethal mutations results in an inviable cell. Synthetic lethal phenotypes are indicative of an interaction between the products of the two mutant genes within the cell.

Biomarkers

A molecule or substance whose detection indicates a particular disease state or treatment response.

Hypoxia

A subnormal concentration of oxygen. In cancer tissue, hypoxia is often the result of abnormal vasculature.

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Helleday, T., Petermann, E., Lundin, C. et al. DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8, 193–204 (2008). https://doi.org/10.1038/nrc2342

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