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Replication origin firing capacity indicates ATR inhibitor sensitivity

A Lumeau1, P L Pfuderer2,3, J A Scarth1

  • 1Centre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK.

Nature Communications
|June 19, 2026
PubMed

Insights

Sensitivity to ATR inhibitors (ATRi) depends on DNA replication origin firing rates. High expression of replication initiation factors predicts ATRi sensitivity, aiding biomarker development for cancer patients.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • ATR inhibitors (ATRi) are in clinical trials for cancer treatment.
  • Mechanisms of ATRi sensitivity and patient stratification biomarkers are currently lacking.

Purpose of the Study:

  • To investigate the mechanisms of ATR inhibitor sensitivity.
  • To identify biomarkers for patient stratification in ATRi therapy.

Main Methods:

  • Parallel proteomics, transcriptomics, and functional analyses were performed.
  • DNA replication origin firing rates were modulated using CDC7 inhibition, CDK2 inhibition, and CDC45 overexpression.
  • ATRi sensitivity was assessed in breast and colorectal cancer cell lines.

Main Results:

  • Sensitive cancer cell lines exhibit higher expression of DNA replication initiation factors and increased origin firing.
  • Higher origin firing rates correlated with increased pan-nuclear γH2AX signals and cell death upon ATRi treatment.
  • High expression of replication initiation factors predicted ATRi sensitivity across various cancer types and acute myeloid leukemia samples.

Conclusions:

  • Lethal origin firing capacity contributes to ATR inhibitor sensitivity.
  • Replication initiation factor expression serves as a predictive biomarker for ATRi sensitivity.
  • This study provides a foundation for developing a multimodal clinical biomarker for ATRi therapy.

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