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State-of-the-art strategies for targeting the DNA damage response in cancer

Abstract

Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.

Key points

  • The DNA damage response (DDR) involves a complex network of genes responsible for sensing and responding to specific types of DNA damage, encompassing specific machineries mediating DNA repair, cell cycle regulation, replication stress responses and apoptosis.

  • Defects in the DDR give rise to genomic instability in cells, aiding in cancer initiation and progression via mutation accumulation, but also providing targetable vulnerabilities relatively specific to cancer cells that can be exploited for clinical benefit with the use of DDR inhibitors.

  • Targeting BRCA1/2-deficient cancers using poly(ADP-ribose) polymerase (PARP) inhibitors is the archetype of synthetic lethality, but now the therapeutic landscape of DDR inhibitors is rapidly expanding; bridging preclinical data on each of these agents to the clinical setting is vital to inform appropriate biomarkers and timing for their use.

  • Preclinical and clinical data on DDR inhibitors indicate that biomarkers of response and resistance extend beyond BRCA1/2 to provide a more inclusive and functionally informed approach to patient selection.

  • Preclinical and clinical research with PARP inhibition has revealed multiple resistance mechanisms across a variety of cancer subtypes, highlighting the need for functional biomarkers and sequential or combination treatment strategies.

  • While impressive clinical responses can be seen rarely with the use of single-agent DDR inhibitors, a multitude of biologically informed combination treatment strategies using a backbone of DDR inhibitors are under development to extend their use to larger populations, while minimizing overlapping toxicities.

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Fig. 1: DNA damage response pathways being targeted in the clinic.
Fig. 2: Timeline of key events leading to FDA approvals of PARP inhibitors in cancer medicine.
Fig. 3: Mechanisms of resistance to PARP inhibitors.
Fig. 4: Biomarker-driven combination strategies to augment PARP inhibitor responses.

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Acknowledgements

The University of Texas MD Anderson Cancer Center (Houston, TX, USA) is supported by the NIH Cancer Center Support Grant CA016672.

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Nature Reviews Clinical Oncology thanks T. Laetsch and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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P.G.P., C.T. and T.A.Y. made substantial contributions to researching data for this article and discussions of content. All authors contributed to writing the article and reviewing/editing of the manuscript before submission.

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Correspondence to Timothy A. Yap.

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G.B.M. has received research support from AstraZeneca, Pfizer and Tesaro, and has been a consultant for AstraZeneca, Pfizer and Tesaro. T.A.Y. has received research support from AstraZeneca, Bayer, Pfizer, Tesaro and Vertex Pharmaceuticals; has served on advisory boards of Aduro, Almac, AstraZeneca, Atrin, Bristol-Myers Squibb, Clovis, EMD Serono, Ignyta, Jansen, Merck, Pfizer, Roche, Seattle Genetics and Vertex Pharmaceuticals; and has received speaker bureau from AstraZeneca, Merck and Tesaro. The other authors declare no competing interests.

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Pilié, P.G., Tang, C., Mills, G.B. et al. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol 16, 81–104 (2019). https://doi.org/10.1038/s41571-018-0114-z

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