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
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Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Genetic Processes Commons, Medical Genetics Commons, Oncology Commons, Radiation Medicine Commons
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Associated Data
PMID: 39235982