Forced Mitotic Entry of S-Phase Cells as a Therapeutic Strategy Induced by Inhibition of WEE1
Forced Mitotic Entry of S-Phase Cells as a Therapeutic Strategy Induced by Inhibition of WEE1
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DOI：
10.1158/2159-8290.cd-11-0320
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发表时间：
2012-06-01
期刊：
影响因子：
28.2
通讯作者：
Turner, Nicholas C.
中科院分区：
文献类型：
--
作者：
Aarts, Marieke;Sharpe, Rachel;Turner, Nicholas C.
在临床前模型中，蛋白激酶WEE 1的抑制与化疗协同作用，WEE 1抑制剂正被探索作为潜在的癌症治疗方法。在这里，我们调查这种协同作用的机制。我们发现，WEE 1抑制迫使S期停滞的细胞直接进入有丝分裂，而不完成DNA合成，导致高度异常的有丝分裂，其特征是分散的染色体和无序的双极纺锤体，最终导致有丝分裂退出与总微核形成和凋亡。这种细胞死亡机制与CHK 1抑制剂相同，在没有化疗的情况下，WEE 1和CHK 1联合抑制迫使有丝分裂从S期进入。我们发现，p53/p21失活与有丝分裂细胞周期蛋白和EZH 2的高表达相结合，使细胞在S期易于进入有丝分裂，细胞依赖于WEE 1来防止过早的细胞周期蛋白依赖性激酶（CDK）1激活。这些功能是侵略性乳腺癌和其他癌症的特点，其中WEE 1抑制剂组合代表一个有前途的靶向therapy.Significance：在这里，我们描述了一种新的机制，诱导癌细胞死亡的WEE 1抑制，迫使有丝分裂直接从S期进入。这种机制代表了侵袭性乳腺癌的潜在治疗方法，特别是三阴性和基底样乳腺癌，因为WEE 1抑制特异性靶向这些癌症中固有的特征：频繁的TP 53突变和有丝分裂细胞周期蛋白和多梳蛋白EZH 2的高表达。Cancer Discov; 2（6）; 524-39. (C)2012年AACR。
Inhibition of the protein kinase WEE1 synergizes with chemotherapy in preclinical models and WEE1 inhibitors are being explored as potential cancer therapies. Here, we investigate the mechanism that underlies this synergy. We show that WEE1 inhibition forces S-phase-arrested cells directly into mitosis without completing DNA synthesis, resulting in highly abnormal mitoses characterized by dispersed chromosomes and disorganized bipolar spindles, ultimately resulting in mitotic exit with gross micronuclei formation and apoptosis. This mechanism of cell death is shared by CHK1 inhibitors, and combined WEE1 and CHK1 inhibition forces mitotic entry from S-phase in the absence of chemotherapy. We show that p53/p21 inactivation combined with high expression of mitotic cyclins and EZH2 predispose to mitotic entry during S-phase with cells reliant on WEE1 to prevent premature cyclin-dependent kinase (CDK) 1 activation. These features are characteristic of aggressive breast, and other, cancers for which WEE1 inhibitor combinations represent a promising targeted therapy.Significance: Here, we describe a novel mechanism of inducing cancer cell death by WEE1 inhibition, forcing mitotic entry directly from S-phase. This mechanism represents a potential therapeutic approach for aggressive breast cancers, and in particular triple-negative and basal-like breast cancers, as WEE1 inhibition specifically targets the features inherent in these cancers: frequent TP53 mutation and high expression of mitotic cyclins and the polycomb protein EZH2. Cancer Discov; 2(6); 524-39. (C) 2012 AACR.