Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers.
Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers.
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连接酶1是铂耐药性的预测因子，其阻滞在XRCC1缺乏上皮卵巢癌中是致命的。
DOI：
10.7150/thno.51456
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发表时间：
2021
期刊：
影响因子：
12.4
通讯作者：
Madhusudan S
中科院分区：
文献类型：
--
作者：
Ali R;Alabdullah M;Algethami M;Alblihy A;Miligy I;Shoqafi A;Mesquita KA;Abdel-Fatah T;Chan SY;Chiang PW;Mongan NP;Rakha EA;Tomkinson AE;Madhusudan S
基本原理：人连接酶（LIG 1、LIG 3和LIG 4）通过催化双链体DNA分子中的单链和双链断裂处的相邻5′-磷酰基和3′-羟基末端之间的磷酸二酯键的形成来维持基因组完整性，所述双链体DNA分子直接由DNA损伤或在复制、重组和DNA修复期间产生。LIG 1、LIG 3和LIG 4是否会影响卵巢癌的发病机制和治疗方法在很大程度上尚不清楚。研究方法：我们研究了LIG 1、LIG 3和LIG 4在上皮性卵巢癌临床队列中的表达[蛋白水平（n=525）和转录水平（n=1075）]，并与临床病理特征和生存结局相关。在临床前，在LIG 1耗尽的卵巢癌细胞中研究铂敏感性。测试LIG 1（L 82）的小分子抑制剂在XRCC 1、BRCA 2或ATM缺陷型癌细胞中的合成致死性应用。结果：LIG 1和LIG 3过表达与侵袭性表型、铂类耐药和低无进展生存期（PFS）相关。相反，LIG 4缺乏与铂类耐药和PFS较差相关。在多变量分析中，LIG 1与不良结局独立相关。在卵巢癌细胞系中，LIG 1缺失增加了铂的细胞毒性。L 82单一疗法在XRCC 1缺陷卵巢癌细胞和3D球体中是合成致死的。细胞毒性增加与DNA双链断裂（DSB）的积累，S期细胞周期阻滞和凋亡细胞增加有关。L 82在BRCA 2缺陷或ATM缺陷癌细胞和3D球状体中也具有选择性毒性。结论：我们提供的证据表明，LIG 1是卵巢癌个性化治疗的一个有吸引力的靶点。
Rationale: The human ligases (LIG1, LIG3 and LIG4) are essential for the maintenance of genomic integrity by catalysing the formation of phosphodiester bonds between adjacent 5′-phosphoryl and 3′-hydroxyl termini at single and double strand breaks in duplex DNA molecules generated either directly by DNA damage or during replication, recombination, and DNA repair. Whether LIG1, LIG3 and LIG4 can influence ovarian cancer pathogenesis and therapeutics is largely unknown. Methods: We investigated LIG1, LIG3 and LIG4 expression in clinical cohorts of epithelial ovarian cancers [protein level (n=525) and transcriptional level (n=1075)] and correlated to clinicopathological features and survival outcomes. Pre-clinically, platinum sensitivity was investigated in LIG1 depleted ovarian cancer cells. A small molecule inhibitor of LIG1 (L82) was tested for synthetic lethality application in XRCC1, BRCA2 or ATM deficient cancer cells. Results: LIG1 and LIG3 overexpression linked with aggressive phenotypes, platinum resistance and poor progression free survival (PFS). In contrast, LIG4 deficiency was associated with platinum resistance and worse PFS. In a multivariate analysis, LIG1 was independently associated with adverse outcome. In ovarian cancer cell lines, LIG1 depletion increased platinum cytotoxicity. L82 monotherapy was synthetically lethal in XRCC1 deficient ovarian cancer cells and 3D-spheroids. Increased cytotoxicity was linked with accumulation of DNA double strand breaks (DSBs), S-phase cell cycle arrest and increased apoptotic cells. L82 was also selectively toxic in BRCA2 deficient or ATM deficient cancer cells and 3D-spheroids. Conclusions: We provide evidence that LIG1 is an attractive target for personalization of ovarian cancer therapy.
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DOI：
10.1158/1078-0432.ccr-16-0564
发表时间：
2017-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
McCormick A;Donoghue P;Dixon M;O'Sullivan R;O'Donnell RL;Murray J;Kaufmann A;Curtin NJ;Edmondson RJ
通讯作者：
Edmondson RJ
影响因子：
4.7
作者：
Michiels, Stefan;Danoy, Patrick;Benhamou, Simone
通讯作者：
Benhamou, Simone
影响因子：
4.8
作者：
Cappelli, E;Taylor, R;Frosina, G
通讯作者：
Frosina, G
影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
影响因子：
6.4
作者：
Abdel-Fatah, Tarek;Sultana, Rebeka;Madhusudan, Srinivasan
通讯作者：
Madhusudan, Srinivasan