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Adefovir dipivoxil induces DNA replication stress and augments ATR inhibitor-related cytotoxicity

Agata Patel1, Elena Seraia2, Daniel Ebner2

  • 1The Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom.

International Journal of Cancer
|March 12, 2020
PubMed

Insights

Combining ATR inhibitors with adefovir dipivoxil overcomes cancer cell resistance. This novel strategy induces replication stress and inhibits ATR signaling, leading to cancer cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Replication stress is prevalent in cancer cells, activating DNA damage repair (DDR) pathways like ATM and Rad3-related (ATR) signaling.
  • ATR signaling protects cancer cells by delaying cell cycle progression and preventing replication fork collapse, promoting proliferation.
  • Resistance to existing DDR-targeting therapies necessitates the development of novel combination treatments.

Purpose of the Study:

  • To identify synergistic combination treatments to overcome resistance in cancer therapies.
  • To screen for compounds that enhance the cytotoxicity of ATR inhibitors.

Main Methods:

  • A drug screen was performed, combining an ATR inhibitor (VE822) with compounds from a bioactive small molecule library.
  • Cytotoxicity was assessed in the presence of ATR, ATM, or DNA-PK inhibition.
  • Mechanisms of action, including replication stress induction and ATR signaling activation, were investigated.

Main Results:

  • Adefovir dipivoxil demonstrated increased cytotoxicity when combined with ATR inhibition, but not ATM or DNA-PK inhibition.
  • Adefovir dipivoxil was found to induce DNA replication stress and activate ATR signaling, stalling cells in S phase.
  • The combination of adefovir dipivoxil and ATR inhibition resulted in increased γH2AX foci, ssDNA accumulation, and cell death, indicating replication catastrophe.

Conclusions:

  • Adefovir dipivoxil is a potent sensitizer to ATR inhibition in cancer cells.
  • Simultaneous induction of replication stress and ATR inhibition represents a promising strategy to induce replication catastrophe and overcome therapeutic resistance.
  • This combination therapy holds potential for treating tumors that rely on ATR signaling for survival.
Keywords:
ATR inhibitorDNA replication stressadefovir dipivoxilpan-nuclear γH2AXreplication catastrophe

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