Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells.
Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells.
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DOI：
10.1158/1078-0432.ccr-12-2621
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发表时间：
2013-02-15
期刊：
影响因子：
--
通讯作者：
Hung MC
中科院分区：
文献类型：
--
作者：
Yamaguchi H;Hsu JL;Chen CT;Wang YN;Hsu MC;Chang SS;Du Y;Ko HW;Herbst R;Hung MC
多项临床试验的结果表明，EGFR酪氨酸激酶抑制剂(TKIs)对野生型(Wt)EGFR肺癌患者的铂类化疗有负面影响，但其潜在的分子机制尚不清楚。确定TKI如何对wt EGFR患者产生负面影响的机制的研究对于未来制定有效的肺癌靶向策略具有重要意义。因此，我们回到了体外研究，调查并确定了对这一现象的可能解释。我们研究了TKIs和顺铂对caspase非依赖性细胞死亡(CID)的影响，以及CID在每种药物和联合治疗中的作用。此外，我们还研究了EGFR信号通路在CID中的作用机制。最后，根据已识别的机制，我们测试了顺铂与SAHA或erastin联合治疗CID的效果。我们发现吉非替尼可抑制顺铂诱导的CID，但不能抑制caspase依赖的细胞死亡。在wt EGFR细胞中，吉非替尼不仅抑制CID，而且不能诱导细胞凋亡，从而影响了顺铂的疗效。吉非替尼抑制EGFR-ERK/AKT激活FOXO3a，进而减少ROS和ROS介导的CID。为了克服这一点，我们发现ROS介导的CID的诱导剂SAHA和erastin强烈地增强了顺铂在wt EGFR细胞中的作用。TKI介导的CID抑制作用是影响化疗疗效的重要因素。此外，FOXO3a通过消除顺铂诱导的ROS而在TKI的负效应中起关键作用。
Results of multiple clinical trials suggest that EGFR tyrosine kinase inhibitors (TKIs) exhibit negative effects on platinum-based chemotherapy in lung cancer patients with wild type (wt) EGFR, but the underlying molecular mechanisms are still uncertain. Studies that identify the mechanism of how TKIs negatively affect patients with wt EGFR are important for future development of effective strategies to target lung cancer. Thus, we returned to in vitro study to investigate and determine a possible explanation for this phenomenon. We investigated the effects of TKIs and cisplatin on caspase-independent cell death (CID) and the role of CID in the efficacy of each drug and the combination. Furthermore, we studied the mechanism how EGFR signaling pathway is involved in CID. Finally, based on the identified mechanism, we tested the combinational effects of cisplatin plus SAHA or erastin on CID. We found that gefitinib inhibited cisplatin-induced CID but not caspase-dependent apoptotic cell death. In wt EGFR cells, gefitinib not only inhibited CID but also failed to induce apoptosis, therefore, compromising the efficacy of cisplatin. Inhibition of EGFR-ERK/AKT by gefitinib activates FOXO3a which in turn reduces reactive oxygen species (ROS) and ROS-mediated CID. To overcome this, we showed that SAHA and erastin, the inducers of ROS-mediated CID, strongly enhance the effect of cisplatin in wt EGFR cells. TKI-mediated inhibition of CID plays an important role of the efficacy of chemotherapy. Moreover, FOXO3a is a key factor in the negative effects of TKI by eliminating cisplatin-induced ROS.