Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress.
Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress.
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DOI：
10.1038/s41418-020-00655-1
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发表时间：
2021-04
影响因子：
12.4
通讯作者：
Higgins GS
中科院分区：
文献类型：
--
作者：
Herbert KJ;Puliyadi R;Prevo R;Rodriguez-Berriguete G;Ryan A;Ramadan K;Higgins GS
T-LAK-originated protein kinase（TOPK）过度表达是多种癌症的特征，但在大多数表型正常组织中不存在。因此，TOPK表达谱分析和TOPK靶向药物制剂的开发为其在靶向治疗剂开发中的未来潜力带来了希望。本文中呈现的结果证实了TOPK作为治疗实体瘤的潜在靶点的价值，并证明了TOPK抑制剂（OTS 964）与放射治疗联合使用时的疗效。使用H460和Calu-6肺癌异种移植物模型，我们表明TOPK的药物抑制增强了分次照射的功效。此外，我们提供了体外证据表明，TOPK在S期起着迄今为止未知的作用，表明TOPK耗竭增加叉停滞和崩溃的条件下的复制应激和外源DNA损伤。TOPK的瞬时敲低被证明会损害从叉停滞的恢复，并增加H460肺癌细胞中复制相关的单链DNA灶的形成。我们还表明，TOPK直接与CHK 1和Cdc 25 c相互作用，这两个关键球员在复制叉崩溃后激活的检查点信号通路。因此，这项研究为TOPK活性支持癌细胞存活的机制提供了新的见解，促进了对复制应激和DNA损伤的响应的检查点信号传导。
T-LAK-originated protein kinase (TOPK) overexpression is a feature of multiple cancers, yet is absent from most phenotypically normal tissues. As such, TOPK expression profiling and the development of TOPK-targeting pharmaceutical agents have raised hopes for its future potential in the development of targeted therapeutics. Results presented in this paper confirm the value of TOPK as a potential target for the treatment of solid tumours, and demonstrate the efficacy of a TOPK inhibitor (OTS964) when used in combination with radiation treatment. Using H460 and Calu-6 lung cancer xenograft models, we show that pharmaceutical inhibition of TOPK potentiates the efficacy of fractionated irradiation. Furthermore, we provide in vitro evidence that TOPK plays a hitherto unknown role during S phase, showing that TOPK depletion increases fork stalling and collapse under conditions of replication stress and exogenous DNA damage. Transient knockdown of TOPK was shown to impair recovery from fork stalling and to increase the formation of replication-associated single-stranded DNA foci in H460 lung cancer cells. We also show that TOPK interacts directly with CHK1 and Cdc25c, two key players in the checkpoint signalling pathway activated after replication fork collapse. This study thus provides novel insights into the mechanism by which TOPK activity supports the survival of cancer cells, facilitating checkpoint signalling in response to replication stress and DNA damage.
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影响因子：
14.9
作者：
Haas KT;Lee M;Esposito A;Venkitaraman AR
通讯作者：
Venkitaraman AR
影响因子：
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作者：
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Sheltzer JM
影响因子：
11.2
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通讯作者：
Drobetsky, Elliot
影响因子：
5.6
作者：
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通讯作者：
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