EGFR-independent EGFR-mutant lung adenocarcinoma cells depend on Bcl-xL and MCL1 for survival.
EGFR-independent EGFR-mutant lung adenocarcinoma cells depend on Bcl-xL and MCL1 for survival.
复制标题
不依赖 EGFR 的 EGFR 突变型肺腺癌细胞的生存依赖于 Bcl-xL 和 MCL1。
DOI：
10.1016/j.lungcan.2019.05.014
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Sakuma Y.
中科院分区：
文献类型：
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作者：
Hirai S;Tada M;Yamaguchi M;Niki T;Sakuma Y.
目的MCL1是一种抗细胞凋亡的BCL2家族成员，在多种恶性肿瘤中高度表达。然而，对MCL1在KRAS突变肺腺癌中的作用知之甚少。在这项研究中，我们旨在阐明MCL1是否可以作为KRAS突变的肺腺癌的治疗靶点，目前还没有有效的分子靶向药物。材料和方法我们检测了MCL1单独或与MEK抑制剂曲美替尼联合应用在多大程度上抑制KRAS突变的肺腺癌细胞H441和EGFR突变的肺腺癌细胞H1975的生长或诱导凋亡。结果MCL1基因敲除不能诱导H441或H1975细胞发生凋亡。然而，MCL1缺失的H441和H1975细胞在曲美替尼存在下发生了凋亡和数量减少。我们还证实了MCL1基因敲除和曲美替尼联合治疗几乎完全抑制了体内H441细胞的生长。结论MCL1基因敲除联合曲美替尼或联合抑制MCL1和Bclxl基因可有效治疗包括KRAS突变亚型在内的肺腺癌。
ObjectivesMCL1 is an anti-apoptotic BCL2 family member that is highly expressed in various malignant tumors. However, little is known about the role of MCL1 inKRAS-mutant lung adenocarcinomas. In this study, we aimed to clarify whether MCL1 could be a therapeutic target inKRAS-mutant lung adenocarcinomas for which no effective molecular targeted drugs are available.Materials and methodsWe examined to what extent MCL1 knockdown either alone or in combination with MEK inhibitor trametinib suppressed growth or induced apoptosis in theKRAS-mutant lung adenocarcinoma cell line H441 andEGFR-mutant lung adenocarcinoma cell line H1975. Furthermore, we investigated the therapeutic effects of dual inhibition of MCL1 and Bcl-xL, another anti-apoptotic BCL2 family member, in these two cell lines.ResultsMCL1 knockdown alone did not induce apoptosis in H441 or H1975 cells. However, MCL1-depleted H441 and H1975 cells underwent apoptosis and decreased in number in the presence of trametinib. We also confirmed that combined therapy by MCL1 knockdown and trametinib almost completely suppressed the growth of H441 cellsin vivo. Moreover, dual knockdown of MCL1 and Bcl-xL induced extensive apoptosis in H441 and H1975 cells.ConclusionThese findings suggest that combined treatments of MCL1 knockdown and trametinib or dual inhibition of MCL1 and Bcl-xL would be effective therapies for lung adenocarcinomas including theKRAS-mutant subtype.