Abstract

Purpose

Radiation-induced activation of cell cycle checkpoints have been of long-standing interest. The WEE1, CHK1 and ATR kinases are key factors in cell cycle checkpoint regulation and are essential for the S and G2 checkpoints. Here, we review the rationale for why inhibitors of WEE1, CHK1 and ATR could be beneficial in combination with radiation.

Conclusions

Combined treatment with radiation and inhibitors of these kinases results in checkpoint abrogation and subsequent mitotic catastrophe. This might selectively radiosensitize tumor cells, as they often lack the p53-dependent G1 checkpoint and therefore rely more on the G2 checkpoint to repair DNA damage. Further affecting the repair of radiation damage, inhibition of WEE1, CHK1 or ATR also specifically suppresses the homologous recombination repair pathway. Moreover, inhibition of these kinases can induce massive replication stress during S phase of the cell cycle, likely contributing to eliminate radioresistant S phase cells. Intriguingly, recent findings suggest that cell cycle checkpoint inhibitors in combination with radiation can also enhance anti-tumor immune effects. Altogether, the expanding knowledge about the functional roles of WEE1, CHK1 and ATR inhibitors support that they are promising candidates for use in combination with radiation treatment.

中文翻译：

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扩大细胞周期检查点抑制剂在放射肿瘤学中的作用

摘要

目的

辐射诱导的细胞周期检查点激活一直受到长期关注。WEE1、CHK1 和 ATR 激酶是细胞周期检查点调节的关键因素，对 S 和 G2 检查点至关重要。在这里，我们回顾了 WEE1、CHK1 和 ATR 抑制剂与放疗联合使用可能有益的基本原理。

结论

与这些激酶的放射和抑制剂联合治疗导致检查点废除和随后的有丝分裂灾难。这可能选择性地使肿瘤细胞放射增敏，因为它们通常缺乏 p53 依赖性 G1 检查点，因此更多地依赖 G2 检查点来修复 DNA 损伤。进一步影响辐射损伤的修复，抑制WEE1、CHK1或ATR也特异性抑制同源重组修复途径。此外，抑制这些激酶可在细胞周期的 S 期诱导大量复制应激，可能有助于消除抗辐射 S 期细胞。有趣的是，最近的研究结果表明，细胞周期检查点抑制剂与放疗相结合也可以增强抗肿瘤免疫作用。总而言之，关于 WEE1 功能角色的知识不断扩展，