ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy

Wang, Mingchao; Ran, Xiaojuan; Leung, Wendy; Kawale, Ajinkya; Saxena, Sneha; Ouyang, Jian; Patel, Parasvi S.; Dong, Yuting; Yin, Tao; Shu, Jian; Manguso, Robert T.; Lan, Li; Wang, Xiao-Fan; Lawrence, Michael S.; Zou, Lee

doi:10.1101/gad.351084.123

Cited by 9 publications

(3 citation statements)

References 47 publications

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“…We treated WT and ΔSTING B16F10 with 5 μM ATRi for 48 h (Fig 4C; S6B) . ATRi-induced IFN-β was largely STING-dependent, as previously observed (19,31).…”

Section: Resultssupporting

confidence: 85%

Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy

Pandya,

Vendetti,

El-Ghoubaira

et al. 2024

Preprint

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DNA damage and cytoplasmic DNA induce type-1 interferon (IFN-1) and potentiate responses to immune checkpoint inhibitors. Our prior work found that inhibitors of the DNA damage response kinase ATR (ATRi) induce IFN-1 and deoxyuridine (dU) incorporation by DNA polymerases, akin to antimetabolites. Whether and how dU incorporation is required for ATRi-induced IFN-1 signaling is not known. Here, we show that ATRi-dependent IFN-1 responses require uracil DNA glycosylase (UNG)-initiated base excision repair and STING. Quantitative analyses of nine distinct nucleosides reveals that ATRi induce dU incorporation more rapidly in UNG wild-type than knockout cells, and that induction of IFN-1 is associated with futile cycles of repair. While ATRi induce similar numbers of micronuclei in UNG wild-type and knockout cells, dU containing micronuclei and cytoplasmic DNA are increased in knockout cells. Surprisingly, DNA fragments containing dU block STING-dependent induction of IFN-1, MHC-1, and PD-L1. Furthermore, UNG knockout sensitizes cells to IFN-γin vitro, and potentiates responses to anti-PD-L1 in resistant tumorsin vivo. These data demonstrate an unexpected and specific role for dU-rich DNA in suppressing STING-dependent IFN-1 responses, and show that UNG-deficient tumors have a heightened response to immune checkpoint inhibitors.STATEMENT OF SIGNIFICANCEAntimetabolites disrupt nucleotide pools and increase dU incorporation by DNA polymerases. We show that unrepaired dU potentiates responses to checkpoint inhibitors in mouse models of cancer. Patients with low tumor UNG may respond to antimetabolites combined with checkpoint inhibitors, and patients with high tumor UNG may respond to UNG inhibitors combined with checkpoint inhibitors.

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“…We treated WT and ΔSTING B16F10 with 5 μM ATRi for 48 h (Fig 4C; S6B) . ATRi-induced IFN-β was largely STING-dependent, as previously observed (19,31).…”

Section: Resultssupporting

confidence: 85%

Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy

Pandya,

Vendetti,

El-Ghoubaira

et al. 2024

Preprint

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“…S6F,G ). Although microsatellite instability clearly confers hypersensitivity to ATR inhibition, it is possible that MMR deficiency in of itself could also play a role ( Wang et al 2023 ). While these results support the potential use of ATR inhibitor monotherapy in MSI-H human cancers, the inherent hypersensitivity of MSI-H cells to ATR inhibitors made it difficult to interpret combinatorial effects of dual WRN/ATR inhibition.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR

Zong,

Koussa,

Cornwell

et al. 2023

Genes Dev.

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Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN—knowledge that would be helpful for informing clinical development of WRN targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system in which the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling us to track the complete sequence of cellular events elicited by acute loss of WRN function. We found that WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner that curiously did not robustly engage checkpoint mechanisms to halt DNA synthesis. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Of potential therapeutic importance, we found no evidence of any generalized mechanism by which MSI-H cancers could adapt to near-complete loss of WRN. However, under conditions of partial WRN degradation, addition of low-dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN. Overall, our results provide the first comprehensive view of molecular events linking upstream inhibition of WRN to subsequent cell death and suggest that dual targeting of WRN and ATR might be a useful strategy for treating MSI-H cancers.

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“…Another striking example of induced synthetic lethality and antitumor immunity after ATR inhibition has been recently reported regarding Mismatch Repair (MMR) deficient cancer cells [ 112 ]. Also, in tumors with high levels of microsatellite instability (MSI-H) that are characterized by decreased levels of WRN helicase, it has been shown that ATR inhibition may potentiate tumor cell death [ 113 ].…”

Section: The Atr Pathway As a Therapeutic Targetmentioning

confidence: 99%

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

Mavroeidi,

Georganta,

Panagiotou

et al. 2024

IJMS

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The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

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ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy

Cited by 9 publications

References 47 publications

Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy

Deoxyuridine-rich cytoplasmic DNA antagonizes STING-dependent innate immune responses and sensitizes resistant tumors to anti-PD-L1 therapy

Comprehensive mapping of cell fates in microsatellite unstable cancer cells supports dual targeting of WRN and ATR

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

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