Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death
Checkpoint Kinase 1 Inhibition Enhances Cisplatin Cytotoxicity and Overcomes Cisplatin Resistance in SCLC by Promoting Mitotic Cell Death
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抑制检查点激酶1增强顺铂的细胞毒性并通过促进有丝分裂细胞死亡克服SCLC中的顺铂耐药
DOI：
10.1016/j.jtho.2019.01.028
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发表时间：
2019-06-01
影响因子：
20.4
通讯作者：
Giaccone, Giuseppe
中科院分区：
文献类型：
--
作者：
Hsu, Wei-Hsun;Zhao, Xiaoliang;Giaccone, Giuseppe
简介：基于铂的化疗仍然是SCLC患者的标准治疗，但治疗的益处往往受到耐药性快速发展的阻碍。到目前为止，还没有针对SCLC的靶向治疗。超过90%的SCLC肿瘤在肿瘤抑制基因肿瘤蛋白p53（p53）中具有突变，肿瘤蛋白p53是一种重要的DNA损伤检查点调节剂，并且这些肿瘤细胞主要依赖于检查点激酶来控制DNA损伤反应。我们研究了在有和没有p53突变的SCLC细胞中，检查点激酶1（Chk1）的抑制是否以及如何影响顺铂的细胞毒性，结果：Chk1抑制剂与顺铂联合应用可协同诱导p53缺陷的SCLC细胞有丝分裂期死亡。这种作用部分通过激活caspase 2和下调E2F转录因子1（E2F1）来调节。此外，Chk1抑制剂prexasertib和AZD 7762在体外和体内增强了顺铂的抗肿瘤活性，并克服了SCLC临床前模型中的顺铂耐药性。我们还观察到，Chk 1的高表达与SCLC患者的总生存率较差。结论：我们的数据帐户Chk 1作为一个潜在的治疗靶点在SCLC，合理的临床开发Chk 1抑制剂和顺铂联合策略治疗SCLC。(C)2019年国际肺癌研究协会。爱思唯尔公司出版All rights reserved.
Introduction: Platinum-based chemotherapy remains the standard treatment for patients with SCLC, but the benefit of the treatment is often hampered by rapid development of drug resistance. Thus far, there is no targeted therapy available for SCLC. More than 90% of SCLC tumors harbor mutations in the tumor suppressor gene tumor protein p53 (p53), an important DNA damage checkpoint regulator, and these tumor cells rely predominantly on the checkpoint kinases to control DNA damage response.Methods: We examined whether and how inhibition of checkpoint kinase 1 (Chk1) affects cisplatin cytotoxicity in SCLC cells with and without p53 mutations, and evaluated the effect of Chk1 inhibitor and cisplatin combination in cisplatin-sensitive and -resistant preclinical models.Results: Inhibition of Chk1 synergized with cisplatin to induce mitotic cell death in the p53-deficeint SCLC cells. The effect was regulated in part through activation of caspase 2 and downregulation of E2F transcription factor 1 (E2F1). Furthermore, Chk1 inhibitors prexasertib and AZD7762 enhanced cisplatin antitumor activity and overcame cisplatin resistance in SCLC preclinical models in vitro an in vivo. We also observed that higher expression of Chk1 was associated with poorer overall survival of patients with SCLC.Conclusions: Our data account Chk1 as a potential therapeutic target in SCLC, and rationalize clinical development of Chk1 inhibitor and cisplatin combinational strategy for the treatment of SCLC. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.