MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells.
MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells.
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DOI：
10.1158/1535-7163.mct-11-0529
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发表时间：
2012-01
影响因子：
5.7
通讯作者：
Altiok S
中科院分区：
文献类型：
--
作者：
Kreahling JM;Gemmer JY;Reed D;Letson D;Bui M;Altiok S
Wee1是G2/M细胞周期检查点控制的关键组成部分，并通过调节CDC2的磷酸化介导细胞周期阻滞。选择性小分子抑制剂MK1775抑制Wee1可破坏G2/M检查点，导致有丝分裂提前进入和细胞死亡。MK1775最近在人类癌症的临床前和临床研究中进行了测试，以增强DNA损伤剂的细胞毒性作用。然而，其在间充质肿瘤中的作用，特别是作为单一药物的作用尚未被探索。在这里，我们研究了MK1775在各种肉瘤细胞系和患者来源的肿瘤外植体中的细胞毒性作用。我们的数据表明，在临床相关浓度的MK1775治疗下，在所有测试的肉瘤中，会导致计划外的有丝分裂和凋亡细胞死亡的开始。在MK1775处理的细胞中，CDC2活性增强，这是通过酪氨酸-15残基抑制磷酸化降低和磷酸化组蛋白H3（有丝分裂进入的标志）表达增加来确定的。Wee1抑制对肉瘤细胞的细胞毒性作用似乎与p53状态无关，因为所有不同p53突变的肉瘤细胞系都对MK1775治疗高度敏感。最后，在患者来源的肉瘤样本中，我们发现MK1775作为单一药物可导致显著的凋亡细胞死亡，这表明抑制Wee1可能是治疗肉瘤的一种新方法。
Wee1 is a critical component of the G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by a selective small molecule inhibitor MK1775 can abrogate G2/M checkpoint resulting in premature mitotic entry and cell death. MK1775 has recently been tested in preclinical and clinical studies of human carcinoma to enhance the cytotoxic effect of DNA damaging agents. However, its role in mesenchymal tumors, especially as a single agent has not been explored. Here we studied the cytotoxic effect of MK1775 in various sarcoma cell lines and patient-derived tumor explants ex vivo. Our data demonstrate that MK1775 treatment at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. In MK1775 treated cells CDC2 activity was enhanced, as determined by decreased inhibitory phosphorylation of tyrosine-15 residue and increased expression of phosphorylated histone H3, a marker of mitotic entry. The cytotoxic effect of Wee1 inhibition on sarcoma cells appears to be independent of p53 status as all sarcoma cell lines with different p53 mutation were highly sensitive to MK1775 treatment. Finally, in patient-derived sarcoma samples we showed that MK1775 as a single agent causes significant apoptotic cell death suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas.