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Targeting replication stress in cancer therapy

Abstract

Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.

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Fig. 1: Illustration of causes of replication stress.
Fig. 2: Schematics of the ATR pathway.
Fig. 3: Fork dynamics regulation by the ATR pathway.
Fig. 4: Drug combinations with ATR–CHK1–WEE1 inhibitors.
Fig. 5: Mechanisms of ATR–CHK1–WEE1 inhibitors to overcome PARP inhibitor resistance.
Fig. 6: Mechanism of immune response sensitization.

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Acknowledgements

This work was funded by the Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence (SPORE) in Ovarian Cancer (NIH/NCI 2P50CA240243) and in Gastrointestinal (GI) Cancer (P50 CA127003). The work was also supported by a Lustgarten Foundation/Stand Up To Cancer Pancreatic Cancer Challenge grant, the Breast Cancer Research Foundation, the Gray Foundation, and the Ludwig Center at Harvard.

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A.D.D. and P.A.K. researched data for the article. A.D.D., P.A.K., A.A.B.A.C. and D.C. contributed substantially to discussion of the content. A.D.D., P.A.K. and A.A.B.A.C. wrote the article. A.D.D., P.A.K., G.I.S. and D.C. reviewed and/or edited the manuscript before submission.

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Correspondence to Alan D. D’Andrea or Panagiotis A. Konstantinopoulos.

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Competing interests

G.I.S. is a consultant/advisory board member for Lilly, Sierra Oncology, Merck-EMD Serono, Pfizer, Astex, Almac, Roche, Bicycle Therapeutics, Fusion Pharmaceuticals, G1 Therapeutics, Bayer, Ip-sen, Cybrexa Therapeutics, Angiex, Daiichi Sankyo and Seattle Genetics, and reports receipt of commercial research grants from Lilly, Sierra Oncology, Merck-EMD Serono and Merck & Co. P.A.K. reports participation in advisory boards from GlaxoSmithKline/Tesaro, Merck, AstraZeneca and Bayer. A.D.D. is a consultant and/or advisory board member for AstraZeneca, Bayer AG, Cedilla Therapeutics, Celgene, Cyteir Therapeutics, Epizyme, GalaxoSmithKline, Ideaya, Impact Therapeutics, LAV Global Management Company Limited. D.C. and A.A.B.A.C. declare no competing interests.

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Glossary

DNA replication fork

A structure that is formed during DNA replication by the unwinding of the DNA double helix, so that the fork has a DNA double helix downstream, towards which the fork progresses, and two single-stranded DNA strands upstream. The replisome, a multiprotein complex present at the DNA fork, is responsible for DNA unwinding and synthesizes new DNA strands.

Mitotic catastrophe

A mechanism of cell death that is the consequence of the appearance of numerous DNA breaks during DNA replication owing to obstructions of the replication fork progression that the cell is not able to overcome.

Replication origin firing

Replication origins are the genomic regions in which DNA replication starts in a two-step process. First, origin licensing occurs during G1 phase when the pre-replication complex assembles to the DNA and identifies the origin sites. Then, origin firing happens in the G1–S transition and S phase by the formation and activation of the replisome, starting DNA replication at the origin site.

Repriming

A DNA damage tolerance pathway through which the replication fork bypasses DNA damage sites. The enzyme primase–polymerase (PRIMPOL) inserts a new primer immediately after the damage site and allows polymerases to restart DNA synthesis.

DNA fibre assay

An in vitro image technique to visualize single DNA molecules and DNA replication forks. Replicating DNA is labelled with two thymidine analogues such as 5-iodo-2′-deoxyuridine (IdU) and 5-chloro-2′-deoxyuridine (CldU), cells are lysed and DNA fibre stretched on glass coverslips. Fibres are then visualized under a microscope by immunofluorescence, allowing the study of replication fork dynamics.

Enhanced response evaluation criteria in solid tumours

Response evaluation criteria in solid tumours (RECIST) sets the criteria to define tumour response or progression to treatments. Enhanced RECIST are modified RECIST criteria that assess changes in the longest diameter of the lesion, allowing earlier detection of response or progression.

Decatenation

The disentanglement of chromosomes during mitosis to allow proper cell division. Sister chromatids entangle as a consequence of DNA replication, but non-replicative entanglements may also occur during interphase.

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da Costa, A.A.B.A., Chowdhury, D., Shapiro, G.I. et al. Targeting replication stress in cancer therapy. Nat Rev Drug Discov 22, 38–58 (2023). https://doi.org/10.1038/s41573-022-00558-5

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