Auranofin Enhances Ibrutinib's Anticancer Activity in EGFR-Mutant Lung Adenocarcinoma
Auranofin Enhances Ibrutinib's Anticancer Activity in EGFR-Mutant Lung Adenocarcinoma
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DOI：
10.1158/1535-7163.mct-17-1173
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发表时间：
2018-10-01
影响因子：
5.7
通讯作者：
Fang, Bingliang
中科院分区：
文献类型：
--
作者：
Hu, Jing;Zhang, Huijuan;Fang, Bingliang
我们之前发现，伊曲替尼在EGFR突变型非小细胞肺癌（NSCLC）中具有抗癌活性。我们最近的一项研究表明，金诺芬，一种用于治疗类风湿性关节炎的金络合物，抑制了PI 3 K/AKT/mTOR通路，并促进了一些NSCLC细胞的凋亡。由于PI 3 K/AKT/mTOR通路是EGFR的主要下游通路之一，因此我们假设在NSCLC细胞中，伊曲替尼的活性可能通过与金诺芬的联合治疗而增强。为此，我们研究了在存在或不存在金诺芬的情况下，EGFR突变型H1975、PC 9和H1650细胞以及EGFR野生型Calu 3和H460细胞中伊曲替尼的剂量反应。虽然低浓度的金诺芬单独显示出轻度的抗癌活性，但其存在显著增强了伊鲁替尼在H1975、PC 9和H1650细胞中的活性（IC 50值降低10- 100倍），但对Calu 3和H460细胞仅具有轻度影响，表明伊鲁替尼的抗EGFR活性在与金诺芬组合时增强。机制分析显示，单独的伊曲替尼在H1975和H1650细胞中诱导了对MEK/ERK通路的显著抑制，而单独的金诺芬抑制了AKT/mTOR通路。伊曲替尼和金诺芬的组合导致两种细胞系中AKT/mTOR和MEK/ERK途径中多个关键节点的表达或磷酸化的抑制显著增强。在小鼠中，伊曲替尼和金诺芬的组合显著抑制H1975异种移植肿瘤的生长，而不诱导明显的毒性作用。我们的结果证明了使用与金诺芬的组合疗法来改善伊曲替尼对NSCLC的抗EGFR活性的可行性。(C)2018年AACR。
We previously found that ibrutinib has anticancer activity in EGFR-mutant non-small cell lung cancer (NSCLC). One of our recent studies showed that auranofin, a gold complex that has been used to treat rheumatoid arthritis, inhibited the PI3K/AKT/mTOR pathway and promoted apoptosis in some NSCLC cells. Because the PI3K/AKT/mTOR pathway is one of the major downstream pathways of EGFR, we hypothesized that ibrutinib's activity might be enhanced by combination therapy with auranofin in NSCLC cells. To this end, we examined ibrutinib's dose responses in EGFR-mutant H1975, PC9, and H1650 cells and in EGFR wild-type Calu3 and H460 cells in the presence or absence of auranofin. Although low concentrations of auranofin alone demonstrated mild anticancer activities, its presence dramatically enhanced ibrutinib's activity in H1975, PC9, and H1650 cells (IC50 value reduced 10- to 100-fold), but had only mild effect on Calu3 and H460 cells, demonstrating that ibrutinib's anti-EGFR activity is enhanced when it is combined with auranofin. A mechanistic analysis revealed that ibrutinib alone induced dramatic inhibition of theMEK/ERK pathway in both H1975 and H1650 cells, whereas auranofin alone inhibited the AKT/mTOR pathway. The combination of ibrutinib and auranofin led to a dramatically enhanced inhibition of the expression or phosphorylation of multiple key nodes in the AKT/mTOR and MEK/ERK pathways in both cell lines. In mice, the combination of ibrutinib and auranofin significantly suppressed the growth of H1975 xeno-grafted tumors without inducing obvious toxic effects. Our results demonstrate the feasibility of improving ibrutinib's anti-EGFR activity for NSCLC using combination therapy with auranofin. (C) 2018 AACR.