Evidence map›Paper›PMID 42321192›Full record

ArticleNature communications2026

Replication origin firing capacity indicates ATR inhibitor sensitivity.

A Lumeau, P L Pfuderer, J A Scarth, E Maniati, M A Guscott, N Shaikh, F B Copley, H Gerdes, S De Angelis, E L Alard and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

A LumeauCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID 0000-0003-0431-3736
P L PfudererDepartment of Pathology, University of Cambridge, Cambridge, UK.ORCID 0000-0002-2349-2920
J A ScarthCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID 0000-0002-0076-6853
E ManiatiCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID 0000-0001-6993-9890
M A GuscottCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID 0000-0003-1307-5450
N ShaikhCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.
F B CopleyCentre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID 0000-0003-1292-7965
H GerdesCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.
S De AngelisCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.
E L AlardCentre for Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID 0000-0002-7804-4121
J WangCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID 0000-0003-2509-9599
P R CutillasCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.ORCID 0000-0002-3426-2274
F K MardakhehDepartment of Biochemistry, University of Oxford, Oxford, UK.ORCID 0000-0003-3896-0827
M A BoemoDepartment of Pathology, University of Cambridge, Cambridge, UK.ORCID 0000-0002-0326-8200
J V FormentDDR Biology, Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.ORCID 0000-0002-7797-2583
S E McClellandCentre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK. s.mcclelland@qmul.ac.uk.ORCID 0000-0002-9987-4511

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Inhibitors of ATR, a central kinase controlling DNA replication origin firing and cellular checkpoints, are undergoing clinical trials, yet mechanisms underpinning sensitivity to ATR inhibitors (ATRi) and patient stratification biomarkers are lacking. Here, we perform in parallel, proteomics, transcriptomics and functional analyses and demonstrate that sensitive cancer cell lines have higher expression of DNA replication initiation factors, and exhibit higher origin firing, increased pan-nuclear γH2AX signals and cell death upon ATRi treatment. ATRi sensitivity is causally associated with origin firing rates, since we could modulate ATRi sensitivity by either up- or down-regulating origin firing capacity using CDC7 inhibition, CDK2 inhibition or CDC45 overexpression in both breast and colorectal cancer cells. High expression of replication initiation factors predicts ATRi sensitivity across cell lines from multiple cancer types and acute myeloid leukemia patient samples. This study reveals a contribution of lethal origin firing capacity to ATR sensitivity, providing key steps towards developing a multimodal clinically applicable biomarker.

Indexed as

Ataxia Telangiectasia Mutated ProteinsProtein Kinase InhibitorsReplication OriginCell Cycle ProteinsCell Line, TumorCyclin-Dependent Kinase 2DNA ReplicationHistonesHumansNuclear ProteinsProtein Serine-Threonine KinasesPyrazinesAtaxia Telangiectasia Mutated ProteinsATR protein, humanCDC7 protein, humanCDK2 protein, humanCell Cycle ProteinsCyclin-Dependent Kinase 2H2AX protein, humanHistonesNuclear ProteinsProtein Kinase InhibitorsProtein Serine-Threonine KinasesPyrazines

Identifiers

PMID42321192
PMCPMC13434684

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.