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Replication Stress is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors
Cancer Research ( IF 12.5 ) Pub Date : 2024-10-16 , DOI: 10.1158/0008-5472.can-23-3603 Asuka Kawai-Kawachi, Madison M. Lenormand, Clémence Astier, Noé Herbel, Meritxell B. Cutrona, Carine Ngo, Marlène Garrido, Thomas Eychenne, Nicolas Dorvault, Laetitia Bordelet, Fei Fei Song, Ryme Bouyakoub, Anastasia Loktev, Antonio Romo-Morales, Clémence Henon, Léo Colmet-Daage, Julien Vibert, Marjorie Drac, Rachel Brough, Etienne Schwob, Oliviano Martella, Guillaume Pinna, Janet M. Shipley, Sibylle Mittnacht, Astrid Zimmermann, Aditi Gulati, Olivier Mir, Axel Le Cesne, Matthieu Faron, Charles Honoré, Christopher J. Lord, Roman M. Chabanon, Sophie Postel-Vinay
Cancer Research ( IF 12.5 ) Pub Date : 2024-10-16 , DOI: 10.1158/0008-5472.can-23-3603 Asuka Kawai-Kawachi, Madison M. Lenormand, Clémence Astier, Noé Herbel, Meritxell B. Cutrona, Carine Ngo, Marlène Garrido, Thomas Eychenne, Nicolas Dorvault, Laetitia Bordelet, Fei Fei Song, Ryme Bouyakoub, Anastasia Loktev, Antonio Romo-Morales, Clémence Henon, Léo Colmet-Daage, Julien Vibert, Marjorie Drac, Rachel Brough, Etienne Schwob, Oliviano Martella, Guillaume Pinna, Janet M. Shipley, Sibylle Mittnacht, Astrid Zimmermann, Aditi Gulati, Olivier Mir, Axel Le Cesne, Matthieu Faron, Charles Honoré, Christopher J. Lord, Roman M. Chabanon, Sophie Postel-Vinay
Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSCRT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP and ATR inhibitors (PARPi, ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically-relevant models of DSRCT, including cell lines, a patient-derived xenograft (PDX)-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2/M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing the sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cGAS/STING innate immune pathway and cell surface expression of PD-L1. Taken together, these findings point towards a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT.
中文翻译:
复制应激是促纤维增生性小圆细胞肿瘤中的一种可操作的遗传脆弱性
结缔组织增生性小圆细胞瘤 (DSRCT) 是一种侵袭性肉瘤亚型,由 EWS-WT1 嵌合转录因子驱动。DSRCT 的预后较差,二十多年来治疗 DSCRT 未取得重大进展。为了确定靶向 DSRCT 的有效治疗方法,我们在 DSRCT 细胞系中进行了高通量药物敏感性筛选,评估了 79 种小分子抑制剂的化疗敏感性特征。DSRCT 细胞对 PARP 和 ATR 抑制剂 (PARPi、ATRi) 作为单一疗法和联合疗法敏感。在三个生物学上不同、临床相关的 DSRCT 模型中使用多个临床 PARPi 和 ATRi 概括了这些影响,包括细胞系、患者来源的异种移植 (PDX) 衍生的类器官模型和细胞系来源的异种移植小鼠模型。从机制上讲,暴露于 PARPi 和 ATRi 的组合会导致 DNA 损伤增加、G2/M 检查点激活、微核积累、复制应激和 R 环形成。EWS-WT1 沉默消除了这些表型,并且是上位性的,具有 R 环溶解酶 RNase H1 的外源性表达,可逆转对 PARPi 和 ATRi 单一疗法的敏感性。PARPi 和 ATRi 的组合还诱导 EWS-WT1 依赖性细胞自主激活 cGAS/STING 先天免疫通路和 PD-L1 的细胞表面表达。综上所述,这些发现表明 EWS-WT1 在产生 R 环依赖性复制应激中的作用,导致可靶向的脆弱性,为 DSRCT 中 PARPi 和 ATRi 的临床评估提供了基本原理。
更新日期:2024-10-16
中文翻译:
复制应激是促纤维增生性小圆细胞肿瘤中的一种可操作的遗传脆弱性
结缔组织增生性小圆细胞瘤 (DSRCT) 是一种侵袭性肉瘤亚型,由 EWS-WT1 嵌合转录因子驱动。DSRCT 的预后较差,二十多年来治疗 DSCRT 未取得重大进展。为了确定靶向 DSRCT 的有效治疗方法,我们在 DSRCT 细胞系中进行了高通量药物敏感性筛选,评估了 79 种小分子抑制剂的化疗敏感性特征。DSRCT 细胞对 PARP 和 ATR 抑制剂 (PARPi、ATRi) 作为单一疗法和联合疗法敏感。在三个生物学上不同、临床相关的 DSRCT 模型中使用多个临床 PARPi 和 ATRi 概括了这些影响,包括细胞系、患者来源的异种移植 (PDX) 衍生的类器官模型和细胞系来源的异种移植小鼠模型。从机制上讲,暴露于 PARPi 和 ATRi 的组合会导致 DNA 损伤增加、G2/M 检查点激活、微核积累、复制应激和 R 环形成。EWS-WT1 沉默消除了这些表型,并且是上位性的,具有 R 环溶解酶 RNase H1 的外源性表达,可逆转对 PARPi 和 ATRi 单一疗法的敏感性。PARPi 和 ATRi 的组合还诱导 EWS-WT1 依赖性细胞自主激活 cGAS/STING 先天免疫通路和 PD-L1 的细胞表面表达。综上所述,这些发现表明 EWS-WT1 在产生 R 环依赖性复制应激中的作用,导致可靶向的脆弱性,为 DSRCT 中 PARPi 和 ATRi 的临床评估提供了基本原理。