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Emerging strategies for cancer therapy by ATR inhibitors

Kimiyoshi Yano1, Bunsyo Shiotani1

  • 1Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Tokyo, Japan.

Cancer Science
|May 16, 2023
PubMed

Insights

Replication stress (RS) in cancer cells triggers DNA damage, but ATR signaling promotes survival and therapeutic resistance. ATR inhibitors (ATRis) show promise for cancer therapy by targeting this dependency.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Replication stress (RS) is a key driver of genomic instability in cancer.
  • The ATR kinase pathway is crucial for managing RS, regulating DNA replication fidelity and cell cycle checkpoints.
  • ATR signaling paradoxically promotes cancer cell survival and therapeutic resistance by enabling RS tolerance.

Purpose of the Study:

  • To review recent advancements in understanding ATR's role in the replication stress response.
  • To discuss the therapeutic implications of targeting ATR with ATR inhibitors (ATRis) in cancer treatment.

Main Methods:

  • Literature review of recent research on ATR signaling in replication stress.
  • Analysis of mechanisms underlying ATR's function in DNA replication and stress response.
  • Evaluation of clinical trial data and biomarker strategies for ATR inhibitor efficacy.

Main Results:

  • Cancer cells with disrupted DNA replication are often addicted to ATR activity for survival.
  • ATR inhibition can sensitize cancer cells to therapy, especially those with specific genetic vulnerabilities.
  • Ongoing clinical trials are exploring ATRis as monotherapies and in combination treatments.

Conclusions:

  • Understanding ATR's dual role in RS response is critical for effective cancer therapy.
  • ATR inhibitors represent a promising therapeutic strategy for cancers exhibiting replication stress vulnerabilities.
  • Targeted combination therapies and biomarker development are essential for optimizing ATR inhibitor efficacy.
Keywords:
ATR inhibitorATR kinaseDNA replication stressbiomarkercancer therapyreplication stress tolerance

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