Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy
Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy
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DOI：
10.1158/1078-0432.ccr-18-4222
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发表时间：
2019-09-01
影响因子：
11.5
通讯作者：
Wang, Tian-Li
中科院分区：
文献类型：
--
作者：
Park, Youngran;Chui, M. Herman;Wang, Tian-Li
目的：在各种类型的人类恶性肿瘤中检测到ARID1A （SWI/SNF染色质重塑复合体的一个组成部分）的体细胞失活突变。ARID1A的缺失损害了DNA损伤的修复。诱导的DNA损伤负担可能增加了癌细胞对PARP依赖性DNA修复的依赖，以维持基因组的完整性，并使其对PARP抑制剂治疗易感性。实验设计：使用等基因ARID1A（-/-）和野生型细胞系来评估DNA损伤反应、DNA紧密度和体内全局丝氨酸/苏氨酸磷酸化蛋白质组学。一组靶向DNA修复途径的抑制剂在ARID1A（-/-）肿瘤的辐照下具有协同抗肿瘤作用。结果：arid1a缺失的子宫内膜细胞表现出持续水平的DNA损伤反应，体内磷蛋白质组学分析进一步支持了这一结果。我们的研究结果表明，ARID1A对于在DNA损伤时建立开放的染色质状态至关重要，这是招募53BP1和RIF1所需的过程，53BP1和RIF1是非同源末端连接（NHEJ）机制的关键介质，DNA损伤。ARID1A（-/-）细胞无法安装NHEJ修复导致对辐射的部分细胞毒性反应。小分子化合物筛选显示，PARP抑制剂与辐射协同作用，增强ARID1A（-/-）细胞的细胞毒性。低剂量放疗和奥拉帕尼联合治疗大大提高了抗肿瘤疗效，使arid1a缺陷肿瘤小鼠长期缓解。结论：arid1a缺陷细胞暴露于外源诱导的DNA断裂（如电离辐射）后，对PARP抑制具有高度敏感性。我们的研究结果为治疗arid1a缺陷恶性肿瘤提供了一种新的生物学策略。
Purpose: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy.Experimental Design: Isogenic ARID1A(-/-) and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A(-/-) tumors.Results: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for recruitment of 53BP1 and RIF1, key mediators of non-homologous end-joining (NHEJ) machinery, to DNA lesions. The inability of ARID1A(-/-) cells to mount NHEJ repair results in a partial cytotoxic response to radiation. Small-molecule compound screens revealed that PARP inhibitors act synergistically with radiation to potentiate cytotoxicity in ARID1A(-/-) cells. Combination treatment with low-dose radiation and olaparib greatly improved antitumor efficacy, resulting in long-term remission in mice bearing ARID1A-deficient tumors.Conclusions: ARID1A-deficient cells acquire high sensitivity to PARP inhibition after exposure to exogenously induced DNA breaks such as ionizing radiation. Our findings suggest a novel biologically informed strategy for treating ARID1A-deficient malignancies.