Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy.
Therapeutic targeting of Chk1 in NSCLC stem cells during chemotherapy.
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DOI：
10.1038/cdd.2011.170
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发表时间：
2012-05
影响因子：
12.4
通讯作者：
中科院分区：
文献类型：
--
作者：
癌症干细胞（SC）化疗耐药可能是导致非小细胞肺癌（NSCLC）患者临床预后不良的原因。为了确定导致NSCLC化疗耐药的分子事件，我们研究了来自NSCLC患者的SCs的DNA损伤反应。我们发现，暴露于化疗药物后，NSCLC-SCs经历细胞周期阻滞，从而允许DNA损伤修复和随后的细胞存活。DNA损伤检查点蛋白激酶（Chk） 1的激活是在接受化疗的NSCLC-SCs中检测到的最早和最重要的事件，与p53状态无关。相比之下，在分化的NSCLC细胞中发现了较弱的Chk1激活，与未分化的NSCLC细胞相比，这对应于对化疗药物的敏感性增加。Chk1抑制剂联合化疗通过诱导过早的细胞周期进展和有丝分裂灾难显著降低体外NSCLC-SC的存活率。一致地，Chk1抑制剂AZD7762和化疗联合施用可以消除体内肿瘤生长，而单独化疗几乎没有效果。联合使用Chk1抑制剂和化疗增加的疗效与小鼠异种移植物中NSCLC-SCs的显著减少有关。综上所述，这些观察结果支持Chk1抑制剂联合化疗更有效治疗非小细胞肺癌的临床评价。
Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
诱导化疗后，非小细胞肺肿瘤的加速再生。
影响因子：
8.8
作者：
El Sharouni, S Y;Kal, H B;Battermann, J J
通讯作者：
Battermann, J J
影响因子：
7.8
作者：
Jin, P;Hardy, S;Morgan, DO
通讯作者：
Morgan, DO
影响因子：
12.4
作者：
Eramo, A.;Lotti, F.;De Maria, R.
通讯作者：
De Maria, R.
DOI：
10.1073/pnas.190030497
发表时间：
2000-09-12
影响因子：
11.1
作者：
Matsuoka, S;Rotman, G;Elledge, SJ
通讯作者：
Elledge, SJ