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

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-10-08 DOI:10.1172/jci.insight.179599
Scott J Bright, Mandira Manandhar, David B Flint, Rishab Kolachina, Mariam Ben Kacem, David Kj Martinus, Broderick X Turner, Ilsa Qureshi, Conor H McFadden, Poliana C Marinello, Simona F Shaitelman, Gabriel O Sawakuchi
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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.

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抑制 ATR 可通过增强 DNA 损伤和抑制 G2 细胞周期停滞使细胞放射致敏。
共济失调毛细血管扩张症和 Rad3 相关蛋白(ATR)是一种关键的 DNA 损伤反应蛋白,可促进 DNA 损伤修复并调节细胞周期的进展。因此,ATR 是细胞对辐射反应的重要组成部分,尤其是在 DNA 损伤反应发生改变和细胞周期检查点异常的癌细胞中。因此,ATR 的药理抑制可能是改善放疗的一种有效的放射增敏策略。我们评估了 ATR 抑制剂 AZD6738 使不同组织学类型的癌细胞系对光子和质子放疗敏感的能力。我们发现,放射增敏是通过持续的 DNA 损伤和 G2 细胞周期停滞来实现的。我们还发现,AZD6738 会增加接受放疗后的微核数量。我们发现,在乳腺癌模型中,放疗与 AZD6738 联合使用可延缓肿瘤生长,延长生存期,而单独使用则无法达到这一效果。将 AZD6738 与光子或质子结合使用还能增加巨噬细胞在肿瘤微环境中的浸润。这些结果为进一步研究 ATR 抑制与放疗和免疫检查点阻断等其他药物的联合应用提供了依据。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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