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./nMethods: 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./nResults: 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./nConclusions: We provide evidence that LIG1 is an attractive target for personalization of ovarian cancer therapy.

中文翻译：

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连接酶 1 是铂耐药性的预测因子，其阻断在 XRCC1 缺陷的上皮性卵巢癌中具有综合致死性


基本原理：人类连接酶（LIG1、LIG3 和 LIG4）通过催化生成的双链 DNA 分子中单链和双链断裂处相邻 5'-磷酸基和 3'-羟基末端之间形成磷酸二酯键，对于维持基因组完整性至关重要直接通过 DNA 损伤或在复制、重组和 DNA 修复过程中发生。 LIG1、LIG3 和 LIG4 是否会影响卵巢癌的发病机制和治疗尚不清楚。/n方法：我们研究了上皮性卵巢癌临床队列中 LIG1、LIG3 和 LIG4 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果相关。临床前，在 LIG1 耗尽的卵巢癌细胞中研究了铂敏感性。 LIG1 (L82) 小分子抑制剂在 XRCC1、BRCA2 或 ATM 缺陷癌细胞中进行了合成致死性应用测试。/n 结果： LIG1 和 LIG3 过度表达与侵袭性表型、铂类耐药和不良无进展生存期 (PFS) 相关。相反，LIG​​4 缺乏与铂耐药和较差的 PFS 相关。在多变量分析中，LIG1 与不良结果独立相关。在卵巢癌细胞系中，LIG1 耗尽会增加铂的细胞毒性。 L82 单一疗法对 XRCC1 缺陷的卵巢癌细胞和 3D 球体具有综合致死性。细胞毒性的增加与 DNA 双链断裂 (DSB) 的积累、S 期细胞周期停滞和凋亡细胞的增加有关。 L82 在 BRCA2 缺陷或 ATM 缺陷的癌细胞和 3D 球体中也具有选择性毒性。/n结论：我们提供的证据表明 LIG1 是卵巢癌个体化治疗的一个有吸引力的靶点。