The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment.
The synthetic lethality of targeting cell cycle checkpoints and PARPs in cancer treatment.
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癌症治疗中靶向细胞周期检查点和 PARP 的综合致死率
DOI：
10.1186/s13045-022-01360-x
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发表时间：
2022-10-17
影响因子：
28.5
通讯作者：
Han, Zhiqiang
中科院分区：
文献类型：
--
作者：
Li, Shuangying;Wang, Liangliang;Wang, Yuanyuan;Zhang, Changyi;Hong, Zhenya;Han, Zhiqiang
细胞持续分裂是癌症的一个标志，其潜在机制是肿瘤基因组学不稳定。在细胞分裂过程中，细胞周期检查点对于维持有序的细胞周期和维持基因组的稳定至关重要。根据细胞周期检查点在细胞周期调控中的不同功能，细胞周期检查点分为DNA损伤检查点和DNA复制应激检查点两类。DNA损伤检查点(ATM-Chk2-P53)主要监测遗传错误并阻止细胞周期进程，以促进DNA修复。不幸的是，参与DNA损伤检查点的基因在人类恶性肿瘤中经常发生突变。相比之下，与DNA复制应激检查点(ATR-CHK1-WEE1)相关的基因在肿瘤中很少发生突变，癌细胞高度依赖这些基因来防止复制灾难和确保基因组的完整性。目前，聚腺苷二磷酸核糖聚合酶抑制剂(PARPI)通过在癌细胞中突变DNA修复途径基因的“合成致死”机制发挥作用。然而，越来越多的患者在长期治疗后获得了PARP抑制剂耐药性。最近的工作表明，靶向细胞周期检查点和PARP的联合治疗可以协同作用，增加DNA错误的数量，破坏DNA修复机制，扰乱细胞周期，从而增加具有DNA修复缺陷或PARP抑制剂耐药的癌细胞的死亡率。我们强调了一个涉及PARP抑制剂和抑制两个主要的细胞周期检查点通路，ATM-CHK2-TP53和ATR-CHK1-WEE1的组合策略。并对其生物学功能、对PARP抑制剂的耐药机制、临床前研究进展和临床试验进行了综述。
Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.
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影响因子：
16
作者：
Buisson R;Boisvert JL;Benes CH;Zou L
通讯作者：
Zou L
影响因子：
16.8
作者：
Berti, Matteo;Chaudhuri, Arnab Ray;Thangavel, Saravanabhavan;Gomathinayagam, Shivasankari;Kenig, Sasa;Vujanovic, Marko;Odreman, Federico;Glatter, Timo;Graziano, Simona;Mendoza-Maldonado, Ramiro;Marino, Francesca;Lucic, Bojana;Biasin, Valentina;Gstaiger, Matthias;Aebersold, Ruedi;Sidorova, Julia M.;Monnat, Raymond J., Jr.;Lopes, Massimo;Vindigni, Alessandro
通讯作者：
Vindigni, Alessandro
影响因子：
11.2
作者：
Anderson VE;Walton MI;Eve PD;Boxall KJ;Antoni L;Caldwell JJ;Aherne W;Pearl LH;Oliver AW;Collins I;Garrett MD
通讯作者：
Garrett MD
影响因子：
64.5
作者：
Barlow JH;Faryabi RB;Callén E;Wong N;Malhowski A;Chen HT;Gutierrez-Cruz G;Sun HW;McKinnon P;Wright G;Casellas R;Robbiani DF;Staudt L;Fernandez-Capetillo O;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A