Abrogation of the G2 Checkpoint by Inhibition of Wee-1 Kinase Results in Sensitization of p53-Deficient Tumor Cells to DNA-Damaging Agents
Abrogation of the G2 Checkpoint by Inhibition of Wee-1 Kinase Results in Sensitization of p53-Deficient Tumor Cells to DNA-Damaging Agents
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DOI：
10.2174/157488410791498824
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发表时间：
2010-01-01
影响因子：
3.2
通讯作者：
Schellens, Jan H. M.
中科院分区：
文献类型：
--
作者：
Leijen, Suzanne;Beijnen, Jos H.;Schellens, Jan H. M.
诱导DNA损伤是一种众所周知的抗癌策略，多年来已经通过多种抗癌药物的应用而得到应用。与正常细胞相比，肿瘤细胞和其他快速分裂的细胞对 DNA 损伤剂引起的 DNA 损伤更敏感。虽然正常细胞可以依靠各种 DNA 修复机制来保护基因组的完整性并促进细胞存活，但大多数肿瘤细胞由于基因变化，在修复 DNA 损伤时面临更大的挑战。 Wee1 是一种酪氨酸激酶，可在 Tyr 15 处磷酸化 CDC2，因此在 G(2) DNA 损伤检查点中发挥关键作用。通过酪氨酸激酶抑制剂抑制 Wee1 的策略是利用受损的 DNA 损伤修复选项，特别是在 p53 失调的细胞中，这会导致 G1 检查点故障。无法依赖 G(1) 检查点的肿瘤细胞对 G(2) 检查点废除更敏感。因此，DNA损伤性化疗与Wee1抑制剂联合使用可能会选择性地使p53缺陷细胞变得敏感，而正常细胞则免受毒性影响。 PD-166285 被描述为一种新型 G(2) 废除剂和 Wee1 抑制剂，但也被描述为一种广谱受体酪氨酸激酶抑制剂。 MK-1775 是一种特异有效的 Wee-1 抑制剂，目前正在进行一项多中心 I 期研究，与吉西他滨、卡铂或顺铂联合治疗晚期实体瘤患者。初步结果显示出良好的耐受性和有前景的抗癌活性。
Inducing DNA damage is a well known strategy for attacking cancer, already being used for many years by the application of a variety of anti cancer drugs. Tumor cells and other rapidly dividing cells are more sensitive to DNA damage caused by DNA damaging agents compared to normal cells. While normal cells can rely on various mechanisms for DNA repair in order to protect the integrity of the genome and to promote cell survival, most tumor cells, due to genetic changes, are more challenged when it comes to repair of DNA damage. Wee1 is a tyrosine kinase that phosphorylates CDC2 at Tyr 15 and as such plays a pivotal role in the G(2) DNA damage checkpoint. The strategy of inhibition of Wee1 by a tyrosine kinase inhibitor is exploiting the impaired options for DNA damage repair especially in cells with deregulated p53, which results in malfunction of the G1 checkpoint. Tumor cells that are unable to rely on the G(1) checkpoint are more sensitive to G(2) checkpoint abrogation. Administration of DNA damaging chemotherapy in combination with a Wee1 inhibitor may therefore selectively sensitize p53 deficient cells, while normal cells are spared from toxicity. PD-166285 has been described as a novel G(2) abrogator and Wee1 inhibitor, but has also been characterized as a broad-spectrum receptor tyrosine kinase inhibitor. MK-1775 is a specific and potent inhibitor of Wee-1 and is currently under investigation in a multi-center phase I study in combination with either gemcitabine, carboplatin or cisplatin in patients with advanced solid tumors. Preliminary results show good tolerability and promising anti-cancer activity.