Faculty, Staff and Student Publications

Publication Date

10-8-2024

Journal

JCI Insight

Abstract

Ataxia telangiectasia and Rad3-related protein (ATR) is a key DNA damage response protein that facilitates DNA damage repair and regulates cell cycle progression. As such, ATR is an important component of the cellular response to radiation, particularly in cancer cells, which show altered DNA damage response and aberrant cell cycle checkpoints. Therefore, ATR's pharmacological inhibition could be an effective radiosensitization strategy to improve radiotherapy. We assessed the ability of an ATR inhibitor, AZD6738, to sensitize cancer cell lines of various histologic types to photon and proton radiotherapy. We found that radiosensitization took place through persistent DNA damage and abrogated G2 cell cycle arrest. We also found that AZD6738 increased the number of micronuclei after exposure to radiotherapy. We found that combining radiation with AZD6738 led to tumor growth delay and prolonged survival relative to radiation alone in a breast cancer model. Combining AZD6738 with photons or protons also led to increased macrophage infiltration at the tumor microenvironment. These results provide a rationale for further investigation of ATR inhibition in combination with radiotherapy and with other agents such as immune checkpoint blockade.

Keywords

Ataxia Telangiectasia Mutated Proteins, Humans, Mice, Animals, DNA Damage, Cell Line, Tumor, G2 Phase Cell Cycle Checkpoints, Radiation-Sensitizing Agents, Pyrimidines, Female, Xenograft Model Antitumor Assays, Tumor Microenvironment, Breast Neoplasms, Morpholines, Sulfoxides, Radiation Tolerance, Pyrazoles, Indoles, Sulfonamides, Cell cycle, DNA repair, Radiation therapy

Comments

Associated Data

PMID: 39235982

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.