Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy
Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy
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DOI：
10.1016/j.trsl.2019.10.003
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发表时间：
2020-03-01
影响因子：
7.8
通讯作者：
Story, Michael D.
中科院分区：
文献类型：
--
作者：
Karanam, Narasimha Kumar;Ding, Lianghao;Story, Michael D.
肿瘤治疗场（TTFields）是一种非侵入性的癌症治疗物理方式，它将低强度、中频和交变电场应用于肿瘤。干扰有丝分裂是描述TTFields对癌细胞影响的第一个机制;然而，TTFields不仅减少了辐射诱导的DNA双链断裂（DSB）的重新连接，而且还诱导了DNA DSB。TTFields产生DNA DSB的机制与复制应激的产生有关，包括DNA复制复合物基因MCM 6和MCM 10以及范可尼贫血途径基因的表达降低。当检查TTFields暴露导致的DNA复制应激标志物时，新复制的DNA长度随着TTFields暴露时间的延长而减少，并且R环形成增加。此外，当细胞暴露于TTFields时，形成了条件脆弱性环境，使细胞更容易受到DNA损伤剂或干扰DNA修复或复制叉维持的剂的影响。TTFields暴露与顺铂或PARP抑制剂联合暴露、TTFields联合PARP抑制剂随后放疗或TTFields暴露结束时单独放疗的效应均具有协同作用。最后，47个关键有丝分裂调节基因的基因表达分析表明，TTFields诱导的有丝分裂畸变和DNA损伤/复制应激事件，虽然彼此密切相关，但可能彼此独立启动。这表明复制应激增强和DNA修复能力降低也是TTFields效应的主要机制，其效应具有治疗意义。
Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects of TTFields on cancer cells; however, TTFields was shown to not only reduce the rejoining of radiation-induced DNA double-strand breaks (DSBs), but to also induce DNA DSBs. The mechanism(s) by which TTFields generates DNA DSBs is related to the generation of replication stress including reduced expression of the DNA replication complex genes MCM6 and MCMIO and the Fanconi's Anemia pathway genes. When markers of DNA replication stress as a result of TTFields exposure were examined, newly replicated DNA length was reduced with TTFields exposure time and there was increased R-loop formation. Furthermore, as cells were exposed to TTFields a conditional vulnerability environment developed which rendered cells more susceptible to DNA damaging agents or agents that interfere with DNA repair or replication fork maintenance. The effect of TTFields exposure with concomitant exposure to cisplatin or PARP inhibition, the combination of TTFields plus concomitant PARP inhibition followed by radiation, or radiation alone at the end of a TTFields exposure were all synergistic. Finally, gene expression analysis of 47 key mitosis regulator genes suggested that TTFields-induced mitotic aberrations and DNA damage/replication stress events, although intimately linked to one another, are likely initiated independently of one another. This suggests that enhanced replication stress and reduced DNA repair capacity are also major mechanisms of TTFields effects, effects for which there are therapeutic implications.