ArticleScientific reports2021
Sensitivity of cells to ATR and CHK1 inhibitors requires hyperactivation of CDK2 rather than endogenous replication stress or ATM dysfunction.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The trial behind it
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Who cites it
8 citing papers in PubMed, 13 citations in OpenAlex.
- Trial
- A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.Annals of medicine · 2026Review
- RMI2 knockdown suppresses ovarian cancer cell growth by impairing DNA damage repair via the ATR/CHK1 signaling pathway.In vitro cellular & developmental biology. Animal · 2026Article
- DNA polymerase beta expression in head & neck cancer modulates the poly(ADP-ribose)-mediated replication checkpoint.DNA repair · 2025Article
- Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non-Small Cell Lung Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2.Cancer research · 2022Article
- The Potential of Topoisomerase Inhibitor-Based Antibody-Drug Conjugates.Pharmaceutics · 2022Review
- Inhibition of Protein Synthesis Induced by CHK1 Inhibitors Discriminates Sensitive from Resistant Cancer Cells.ACS pharmacology & translational science · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
DNA damage activates cell cycle checkpoint proteins ATR and CHK1 to arrest cell cycle progression, providing time for repair and recovery. Consequently, inhibitors of ATR (ATRi) and CHK1 (CHK1i) enhance damage-induced cell death. Intriguingly, both CHK1i and ATRi alone elicit cytotoxicity in some cell lines. Sensitivity has been attributed to endogenous replications stress, but many more cell lines are sensitive to ATRi than CHK1i. Endogenous activation of the DNA damage response also did not correlate with drug sensitivity. Sensitivity correlated with the appearance of γH2AX, a marker of DNA damage, but without phosphorylation of mitotic markers, contradicting suggestions that the damage is due to premature mitosis. Sensitivity to ATRi has been associated with ATM mutations, but dysfunction in ATM signaling did not correlate with sensitivity. CHK1i and ATRi circumvent replication stress by reactivating stalled replicons, a process requiring a low threshold activity of CDK2. In contrast, γH2AX induced by single agent ATRi and CHK1i requires a high threshold activity CDK2. Hence, phosphorylation of different CDK2 substrates is required for cytotoxicity induced by replication stress plus ATRi/CHK1i as compared to their single agent activity. In summary, sensitivity to ATRi and CHK1i as single agents is elicited by premature hyper-activation of CDK2.
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Registered trials
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