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Therapeutic opportunities within the DNA damage response

Key Points

  • The purpose of this Analysis article is to comprehensively overview the DNA damage response (DDR) pathways, assess current drug development activities in this area, examine the emerging understanding of how defects in genome stability mechanisms contribute to cancer and, by utilizing systematic bioinformatics and chemogenomic approaches, highlight the considerable opportunities these pathways offer as targets for new cancer treatments.

  • We first provide a brief review of the different types of DNA damage and the DDR pathways and mechanisms that have evolved to repair them, how defects in these systems promote cancer, how some existing therapies operate via DNA damage, and the emerging concept of pharmacological synthetic lethality that takes advantage of cancer-associated DDR defects.

  • We then describe our assembly of an expert-curated set of 450 proteins involved in the DDR and in closely associated processes such as chromatin remodelling and chromosome segregation. We present their assignment to specific DDR pathways and the functional interactions within and between pathways. We classify these proteins into functional classes and discuss the current knowledge of their involvement in cancer.

  • We then undertake a systematic bioinformatics analysis of the DDR proteins in 15 different cancers, using data from The Cancer Genome Atlas. We analyse protein coding mutations, copy-number variation and overexpression and underexpression. We find that DDR processes that are commonly mutated differ markedly between different cancer types, but note that every DDR process is functionally impaired to some extent in one or more cancer type, providing many opportunities for drug therapy but with substantial challenges for optimal targeting.

  • We explore the concept of synthetic lethality and document current examples, including pharmacological inhibition of poly(ADP-ribose) polymerase 1 (PARP1) in homologous recombination-deficient cancers. We use data from whole-genome negative genetic analysis of yeast to identify further opportunities for synthetic lethal relationships with the curated DDR proteins that may be amenable to drug discovery.

  • Next we document the limited set of drug discovery projects that are currently targeting DDR proteins and discuss the application of druggability analysis to expand the therapeutic opportunities among these proteins.

  • Finally, we use a combination of approaches to identify a number of classes among the DDR proteins — particularly DNA helicases and scaffold proteins — that should have particular promise as cancer drug targets. We also highlight potentially druggable targets for each of the DDR pathways.

Abstract

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets.

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Figure 1: DNA damage proteins with known small-molecule modulators.
Figure 2: A network view of the DNA damage response.
Figure 3: Functional annotation of the DNA damage response pathways.
Figure 4: Pathway-based disruption diagrams for individual cancer types.
Figure 5: Predicted human synthetic lethality or sensitivity within the DNA damage response.

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Acknowledgements

The authors would like to thank the following principal investigators from the Sussex Genome Damage and Stability Centre for help with curating the DDR gene list and for providing deep insights into the pathways and networks that make up the DDR: A. Carr, J. Murray, J. Downs, E. Hoffmann, A. Lehmann, P. Jeggo, A. Bianchi, J. Baxter, K. Caldecott and V. Savic. The authors would also like to thank C. Richardson and J. Tym for technical assistance, A. Eyre-Walker and C. Parry-Morris for useful discussions, and A. Carr, P. Beswick and P. Workman for critical reading of the manuscript. This work was supported by a Daphne Jackson Fellowship funded by the Medical Research Council (F.M.G.P.); Cancer Research UK core funding to the Cancer Therapeutics Unit at the Institute of Cancer Research in London C309/A11566 (B.A.-L.); and a Cancer Research UK Programme Grant C302/A14532 (L.H.P.). Author contributions: L.H.P., S.E.W., B.A.-L. and F.M.G.P. conceived the project; F.M.G.P. and B.A.-L. designed the analysis; A.C.S., B.A.-L. and F.M.G.P. performed the data analysis and informatics; and L.H.P., B.A.-L. and F.M.G.P. wrote the paper.

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Correspondence to Bissan Al-Lazikani or Frances M. G. Pearl.

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B.A.-L. is an employee of The Institute of Cancer Research (ICR), which has a commercial interest in inhibitors in oncology targets, and operates a 'Rewards to Inventors' scheme. L.H.P. is a director and shareholder in Domainex Limited a biotechnology company, developing novel drugs for a range of human diseases. S.E.W. is a consultant for BioCrea GmbH.

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Supplementary information

Supplementary information S1 (table)

Current DDR targets with drugs or compounds in clinical trials (PDF 182 kb)

Supplementary information S2 (box)

Methods (PDF 348 kb)

Supplementary information S3 (table)

Hierarchical classification of DDR genes (PDF 364 kb)

Supplementary information S4 (figure)

(ZIP 194 kb)

Supplementary information S5 (table)

Genes within the DDR implicated in genetic diseases (PDF 250 kb)

Supplementary information S6 (table)

Genes predicted to be oncogenes or tumour suppressors according to the 20:20 rule (PDF 105 kb)

Supplementary information S7 (table)

Mutational frequency per disease (PDF 143 kb)

Supplementary information S8 (table)

Pathway disruption of the DDR in 15 TCGA cancers (PDF 271 kb)

Supplementary information S9 (figure)

(ZIP 27 kb)

Supplementary information S10 (table)

SSL predictions (PDF 1367 kb)

Supplementary information S11 (table)

Targets with small molecule modulators (PDF 121 kb)

Supplementary information S12 (table)

Ligand druggability predictions (PDF 154 kb)

Supplementary information S13 (table)

Structure druggability predictions (PDF 322 kb)

Supplementary information S14 (table)

Network druggability predictions (PDF 315 kb)

Supplementary information S15 (figure)

(ZIP 182 kb)

Supplementary information S16 (table)

Kinases that regulate DDR proteins (PDF 402 kb)

Supplementary information S17 (table)

DDR proteins with reported ubiquitination sites (PDF 1569 kb)

Supplementary information S18 (table)

E3 ligases with reported interactions with DDR proteins (PDF 287 kb)

Supplementary information S19 (table)

DUBs reported to interact with DDR proteins (PDF 232 kb)

Supplementary information S20 (table)

Duggability predictions for best pathway-based candidates (PDF 156 kb)

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Pearl, L., Schierz, A., Ward, S. et al. Therapeutic opportunities within the DNA damage response. Nat Rev Cancer 15, 166–180 (2015). https://doi.org/10.1038/nrc3891

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