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ATR inhibition radiosensitizes cells through augmented DNA damage and G2 cell cycle arrest abrogation

Scott J Bright1, Mandira Manandhar1, David B Flint1

  • 1Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

JCI Insight
|September 5, 2024
PubMed

Insights

Combining ATR inhibition with radiation therapy, including photon and proton beams, enhances cancer treatment by causing persistent DNA damage and improving tumor growth delay. This approach also increases macrophage infiltration in the tumor microenvironment.

Area of Science:

  • Oncology
  • Radiation Oncology
  • Molecular Biology

Background:

  • Ataxia telangiectasia and Rad3-related protein (ATR) is crucial for DNA damage response and cell cycle regulation.
  • Cancer cells often have altered DNA damage responses, making them vulnerable to radiosensitization strategies.
  • ATR's role in DNA repair and cell cycle checkpoints highlights its potential as a therapeutic target in radiotherapy.

Purpose of the Study:

  • To evaluate the radiosensitizing potential of the ATR inhibitor AZD6738 in various cancer cell lines.
  • To investigate the effects of combining AZD6738 with photon and proton radiotherapy.
  • To assess the impact of this combination therapy on tumor growth, survival, and the tumor microenvironment.

Main Methods:

  • Treatment of diverse cancer cell lines with AZD6738 and photon/proton radiotherapy.
  • Assessment of DNA damage, cell cycle arrest (G2), and micronuclei formation.
  • In vivo studies using a breast cancer model to evaluate tumor growth delay and survival.
  • Analysis of immune cell infiltration, specifically macrophages, within the tumor microenvironment.

Main Results:

  • AZD6738 effectively sensitized cancer cells to both photon and proton radiotherapy.
  • Radiosensitization was mediated by persistent DNA damage and abrogation of G2 cell cycle arrest.
  • The combination therapy led to increased micronuclei formation post-radiotherapy.
  • In a breast cancer model, combined AZD6738 and radiation significantly delayed tumor growth and prolonged survival.
  • Increased macrophage infiltration was observed in tumors treated with AZD6738 and radiotherapy.

Conclusions:

  • Pharmacological inhibition of ATR with AZD6738 is a promising strategy for radiosensitization in various cancer types.
  • Combining ATR inhibition with radiotherapy enhances anti-tumor effects through DNA damage and cell cycle disruption.
  • The combination therapy modulates the tumor microenvironment by increasing macrophage infiltration, suggesting potential for immunotherapy combinations.
  • Further clinical investigation of ATR inhibitors with radiotherapy is warranted.
Keywords:
Cell cycleDNA repairOncologyRadiation therapy

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