Vriend Lianne E M, De Witt Hamer Philip C, Van Noorden Cornelis J F, Würdinger Thomas
Neurosurgical Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Neuro-oncology Research Group, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Biochim Biophys Acta. 2013 Dec;1836(2):227-35. doi: 10.1016/j.bbcan.2013.05.002. Epub 2013 May 31.
One of the hallmarks of cancer is genomic instability controlled by cell cycle checkpoints. The G1 and G2 checkpoints allow DNA damage responses, whereas the mitotic checkpoint enables correct seggregation of the sister chromosomes to prevent aneuploidy. Cancer cells often lack a functional G1 arrest and rely on G2 arrest for DNA damage responses. WEE1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancer types. Inhibition of WEE1 is a promising strategy in cancer therapy in combination with DNA-damaging agents, especially when cancer cells harbor p53 mutations, as it causes mitotic catastrophy when DNA is not repaired during G2 arrest. Cancer cell response to WEE1 inhibition monotherapy has also been demonstrated in various types of cancer, including p53 wild-type cancers. We postulate that chromosomal instability can explain tumor response to WEE1 monotherapy. Therefore, chromosomal instability may need to be taken into account when determining the most effective strategy for the use of WEE1 inhibitors in cancer therapy.
癌症的一个标志是由细胞周期检查点控制的基因组不稳定。G1和G2检查点允许DNA损伤反应，而有丝分裂检查点能使姐妹染色体正确分离以防止非整倍体。癌细胞通常缺乏功能性的G1期阻滞，而是依靠G2期阻滞来进行DNA损伤反应。WEE1激酶是G2检查点的重要调节因子，在多种癌症类型中过表达。抑制WEE1是癌症治疗中与DNA损伤剂联合使用的一种有前景的策略，特别是当癌细胞存在p53突变时，因为当DNA在G2期阻滞期间未修复时，它会导致有丝分裂灾难。癌细胞对WEE1抑制单一疗法的反应也已在包括p53野生型癌症在内的各种癌症类型中得到证实。我们推测染色体不稳定可以解释肿瘤对WEE1单一疗法的反应。因此，在确定WEE1抑制剂在癌症治疗中最有效的使用策略时，可能需要考虑染色体不稳定因素。
