Ng Victor, Sinha Sonali, Novaj Ardijana, Ma Jennifer, McDermott Niamh, Pei Xin, Longhini Ana Leda F, Grimsley Helen, Gardner Rui, Rosen Ezra, Powell Simon N, Pareja Fresia, Mandelker Diana, Khan Atif, Setton Jeremy, Roulston Anne, Morris Stephen, Koehler Maria, Lee Nancy, Reis-Filho Jorge, Riaz Nadeem
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2024 Dec 16;30(24):5643-5656. doi: 10.1158/1078-0432.CCR-24-0154.
The importance of the DNA damage response in mediating effects of radiotherapy (RT) has galvanized efforts to target this pathway with radiosensitizers. Yet early clinical trials of this approach have failed to yield a benefit in unselected populations. We hypothesized that ataxia-telangiectasia mutated (Atm)-null tumors would demonstrate genotype-specific synergy between RT and an inhibitor of the DNA damage response protein ataxia-telangiectasia and Rad3-related (ATR) kinase.
We investigated the synergistic potential of the ATR inhibitor (ATRi) RP-3500 and RT in two Atm-null and isogenic murine models, both in vitro and in vivo. Staining of γ-H2AX foci, characterization of the immune response via flow cytometry, and tumor rechallenge experiments were performed to elucidate the mechanism of interaction. To examine genotype specificity, we tested the interaction of ATRi and RT in a Brca1-null model. Finally, patients with advanced cancer with ATM alterations were enrolled in a phase I/II clinical trial to validate preclinical findings.
Synergy between RP-3500 and RT was confirmed in Atm-null lines in vitro, characterized by an accumulation of DNA double-strand breaks. In vivo, Atm-null tumor models had higher rates of durable control with RT and ATRi than controls. In contrast, there was no synergy in tumors lacking Brca1. Analysis of the immunologic response indicated that efficacy is largely mediated by cell-intrinsic mechanisms. Lastly, early results from our clinical trial showed complete responses in patients.
Genotype-directed radiosensitization with ATRi and RT can unleash significant therapeutic benefit and could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments. See related commentary by Schrank and Colbert, p. 5505.
DNA损伤反应在介导放射治疗（RT）效果中的重要性促使人们努力用放射增敏剂靶向该途径。然而，这种方法的早期临床试验未能在未选择的人群中产生益处。我们假设，共济失调毛细血管扩张症突变（Atm）缺失的肿瘤将在RT与DNA损伤反应蛋白共济失调毛细血管扩张症和Rad3相关（ATR）激酶抑制剂之间表现出基因型特异性协同作用。
我们在两种Atm缺失的同基因小鼠模型中，在体外和体内研究了ATR抑制剂（ATRi）RP - 3500与RT的协同潜力。进行了γ - H2AX焦点染色、通过流式细胞术表征免疫反应以及肿瘤再激发实验，以阐明相互作用的机制。为了检验基因型特异性，我们在Brca1缺失模型中测试了ATRi与RT的相互作用。最后，招募了患有ATM改变的晚期癌症患者参加I/II期临床试验，以验证临床前研究结果。
在体外的Atm缺失细胞系中证实了RP - 3500与RT之间的协同作用，其特征是DNA双链断裂的积累。在体内，Atm缺失的肿瘤模型与对照组相比，RT和ATRi联合使用时具有更高的持久控制率。相比之下，缺乏Brca1的肿瘤没有协同作用。免疫反应分析表明，疗效主要由细胞内在机制介导。最后，我们临床试验的早期结果显示患者有完全缓解。
使用ATRi和RT进行基因型导向的放射增敏可带来显著的治疗益处，并可能代表一种开发更有效的基于合成细胞毒性RT的联合治疗方法的新途径。见Schrank和Colbert的相关评论，第5505页。
