Targeting Mre11 overcomes platinum resistance and induces synthetic lethality in XRCC1 deficient epithelial ovarian cancers.
Targeting Mre11 overcomes platinum resistance and induces synthetic lethality in XRCC1 deficient epithelial ovarian cancers.
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DOI：
10.1038/s41698-022-00298-0
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发表时间：
2022-07-19
影响因子：
7.9
通讯作者：
Madhusudan S
中科院分区：
文献类型：
--
作者：
Alblihy A;Ali R;Algethami M;Shoqafi A;Toss MS;Brownlie J;Tatum NJ;Hickson I;Moran PO;Grabowska A;Jeyapalan JN;Mongan NP;Rakha EA;Madhusudan S
铂耐药是卵巢癌的临床挑战。铂化剂诱导DNA损伤，激活Mre11核酸酶定向DNA损伤信号和反应（DDR）。DDR的上调可能促进化疗耐药。在这里，我们全面评估了Mre11在上皮性卵巢癌中的作用。在接受铂类化疗的临床队列中（n = 331）， Mre11蛋白过表达与侵袭性表型和不良无进展生存期（PFS）相关（p = 0.002）。在卵巢癌基因组图谱（TCGA）队列（n = 498）中，在浆液性肿瘤亚组（5%）中观察到Mre11基因扩增，其与Mre11 mRNA水平高度相关（p < 0.0001）。Mre11水平的改变与可影响铂敏感性的全基因组改变有关。在转录组水平（n = 1259）， Mre11过表达与不良PFS相关（p = 0.003）。ROC分析显示，对铂类化疗的反应曲线下面积（AUC）为0.642。临床前，通过基因敲低或小分子抑制剂（Mirin）阻断Mre11的消耗逆转了卵巢癌细胞和3D球体模型中的铂耐药性。重要的是，Mre11抑制在铂敏感的XRCC1缺陷卵巢癌细胞和3d球体中具有合成致死性。选择性细胞毒性与DNA双链断裂（DSB）积累、s期细胞周期阻滞和细胞凋亡增加有关。我们的结论是，开发Mre11抑制剂是治疗卵巢癌铂致敏和合成致死性的一种可行的临床策略。
Platinum resistance is a clinical challenge in ovarian cancer. Platinating agents induce DNA damage which activate Mre11 nuclease directed DNA damage signalling and response (DDR). Upregulation of DDR may promote chemotherapy resistance. Here we have comprehensively evaluated Mre11 in epithelial ovarian cancers. In clinical cohort that received platinum- based chemotherapy (n = 331), Mre11 protein overexpression was associated with aggressive phenotype and poor progression free survival (PFS) (p = 0.002). In the ovarian cancer genome atlas (TCGA) cohort (n = 498), Mre11 gene amplification was observed in a subset of serous tumours (5%) which correlated highly with Mre11 mRNA levels (p < 0.0001). Altered Mre11 levels was linked with genome wide alterations that can influence platinum sensitivity. At the transcriptomic level (n = 1259), Mre11 overexpression was associated with poor PFS (p = 0.003). ROC analysis showed an area under the curve (AUC) of 0.642 for response to platinum-based chemotherapy. Pre-clinically, Mre11 depletion by gene knock down or blockade by small molecule inhibitor (Mirin) reversed platinum resistance in ovarian cancer cells and in 3D spheroid models. Importantly, Mre11 inhibition was synthetically lethal in platinum sensitive XRCC1 deficient ovarian cancer cells and 3D-spheroids. Selective cytotoxicity was associated with DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and increased apoptosis. We conclude that pharmaceutical development of Mre11 inhibitors is a viable clinical strategy for platinum sensitization and synthetic lethality in ovarian cancer.
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实现癌症基因组数据的共同愿景。
DOI：
10.1056/nejmp1607591
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Grossman RL;Heath AP;Ferretti V;Varmus HE;Lowy DR;Kibbe WA;Staudt LM
通讯作者：
Staudt LM
影响因子：
50.3
作者：
Berger AC;Korkut A;Kanchi RS;Hegde AM;Lenoir W;Liu W;Liu Y;Fan H;Shen H;Ravikumar V;Rao A;Schultz A;Li X;Sumazin P;Williams C;Mestdagh P;Gunaratne PH;Yau C;Bowlby R;Robertson AG;Tiezzi DG;Wang C;Cherniack AD;Godwin AK;Kuderer NM;Rader JS;Zuna RE;Sood AK;Lazar AJ;Ojesina AI;Adebamowo C;Adebamowo SN;Baggerly KA;Chen TW;Chiu HS;Lefever S;Liu L;MacKenzie K;Orsulic S;Roszik J;Shelley CS;Song Q;Vellano CP;Wentzensen N;Cancer Genome Atlas Research Network;Weinstein JN;Mills GB;Levine DA;Akbani R
通讯作者：
Akbani R
影响因子：
4.7
作者：
Fekete, Janos Tibor;Osz, Agnes;Gyorffy, Balazs
通讯作者：
Gyorffy, Balazs
影响因子：
14.8
作者：
Dupre, Aude;Boyer-Chatenet, Louise;Gautier, Jean
通讯作者：
Gautier, Jean
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。
影响因子：
12.4
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
通讯作者：
Madhusudan S