Emerging strategies for cancer therapy by ATR inhibitors.
Emerging strategies for cancer therapy by ATR inhibitors.
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DNA 复制应激 (RS) 会导致癌细胞的基因组不稳定和脆弱性。为了对抗 RS，细胞进化出了各种涉及 ATR 激酶信号通路的机制，该通路调节起源放电、细胞周期检查点和分叉稳定，以确保复制的保真度。然而，ATR 信号传导还可以通过驱动 RS 耐受性来减轻 RS 以支持细胞存活，从而导致治疗耐药。含有基因突变和其他破坏正常 DNA 复制的变化的癌细胞会增加 DNA 损伤的风险和 RS 水平，从而导致对 ATR 活性的持续复制成瘾，并对使用 ATR 抑制剂 (ATRis) 的治疗方法敏感。因此，目前正在进行临床试验来评估 ATR 作为单一疗法或与其他药物和生物标志物联合疗法的疗效。在这篇综述中，我们讨论了阐明 ATR 在 RS 反应中发挥作用的机制及其在利用 ATRis 时的治疗相关性方面的最新进展。共济失调毛细血管扩张症和 Rad3 相关抑制剂 (ATRis) 的潜在作用模型取决于 DNA 复制应激 (RS) 水平。由于癌基因激活和/或 DNA 损伤反应缺陷，癌细胞通常具有增加的 RS，并通过获得 ATR 介导的 RS 耐受机制而变得对 RS 耐受，从而赋予使用 ATRis 的治疗方法的敏感性。由 ATR 单一疗法或与其他药物联合诱导的 RS 水平超过阈值，可通过复制灾难和有丝分裂灾难导致细胞死亡。
DNA replication stress (RS) causes genomic instability and vulnerability in cancer cells. To counteract RS, cells have evolved various mechanisms involving the ATR kinase signaling pathway, which regulates origin firing, cell cycle checkpoints, and fork stabilization to secure the fidelity of replication. However, ATR signaling also alleviates RS to support cell survival by driving RS tolerance, thereby contributing to therapeutic resistance. Cancer cells harboring genetic mutations and other changes that disrupt normal DNA replication increase the risk of DNA damage and the levels of RS, conferring addiction to ATR activity for sustainable replication and susceptibility to therapeutic approaches using ATR inhibitors (ATRis). Therefore, clinical trials are currently being conducted to evaluate the efficacy of ATRis as monotherapies or in combination with other drugs and biomarkers. In this review, we discuss recent advances in the elucidation of the mechanisms by which ATR functions in the RS response and its therapeutic relevance when utilizing ATRis. Potential models of action of ataxia telangiectasia and Rad3‐related inhibitors (ATRis) depending on DNA replication stress (RS) levels. Cancer cells often harbor increased RS because of oncogene activation and/or DNA damage response defects and become RS tolerant by acquiring ATR‐mediated RS tolerance mechanisms, thereby conferring susceptibility to therapeutic approaches using ATRis. RS at levels over the threshold, induced by ATRis as monotherapies or in combination with other drugs, can lead to cell death through replication catastrophe and mitotic catastrophe.
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DOI：
10.1083/jcb.201008076
发表时间：
2011-01-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Göhler T;Sabbioneda S;Green CM;Lehmann AR
通讯作者：
Lehmann AR
DOI：
10.1016/s1470-2045(20)30180-7
发表时间：
2020-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Konstantinopoulos PA;Cheng SC;Wahner Hendrickson AE;Penson RT;Schumer ST;Doyle LA;Lee EK;Kohn EC;Duska LR;Crispens MA;Olawaiye AB;Winer IS;Barroilhet LM;Fu S;McHale MT;Schilder RJ;Färkkilä A;Chowdhury D;Curtis J;Quinn RS;Bowes B;D'Andrea AD;Shapiro GI;Matulonis UA
通讯作者：
Matulonis UA
影响因子：
11.2
作者：
Gilad O;Nabet BY;Ragland RL;Schoppy DW;Smith KD;Durham AC;Brown EJ
通讯作者：
Brown EJ
DOI：
10.1126/science.aan6490
发表时间：
2018-01-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kabeche L;Nguyen HD;Buisson R;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