The 4th Department of Internal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China.
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mol Cancer Ther. 2018 Oct;17(10):2156-2163. doi: 10.1158/1535-7163.MCT-17-1173. Epub 2018 Jul 31.
We previously found that ibrutinib has anticancer activity in -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 -mutant H1975, PC9, and H1650 cells and in 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 (IC 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 the MEK/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 xenografted 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. .
我们之前发现伊布替尼在 - 突变非小细胞肺癌（NSCLC）中有抗癌活性。我们最近的一项研究表明，金复合物金诺芬（一种用于治疗类风湿关节炎的药物）抑制了 PI3K/AKT/mTOR 通路，并促进了一些 NSCLC 细胞的凋亡。由于 PI3K/AKT/mTOR 通路是 EGFR 的主要下游通路之一，我们假设伊布替尼与金诺芬联合治疗可能会增强 NSCLC 细胞中的活性。为此，我们在存在或不存在金诺芬的情况下，检查了伊布替尼在 - 突变的 H1975、PC9 和 H1650 细胞以及野生型 Calu3 和 H460 细胞中的剂量反应。虽然单独使用低浓度的金诺芬表现出轻微的抗癌活性，但它的存在显著增强了伊布替尼在 H1975、PC9 和 H1650 细胞中的活性（IC 值降低了 10-100 倍），但对 Calu3 和 H460 细胞只有轻微的影响，表明伊布替尼的抗 EGFR 活性在与金诺芬联合使用时增强。机制分析表明，伊布替尼单独使用在 H1975 和 H1650 细胞中强烈抑制了 MEK/ERK 通路，而金诺芬单独使用抑制了 AKT/mTOR 通路。伊布替尼和金诺芬的联合使用导致两条细胞系中 AKT/mTOR 和 MEK/ERK 通路的多个关键节点的表达或磷酸化被显著抑制。在小鼠中，伊布替尼和金诺芬的联合使用显著抑制了 H1975 异种移植瘤的生长，而没有引起明显的毒性作用。我们的结果表明，使用金诺芬联合治疗可提高伊布替尼对 NSCLC 的抗 EGFR 活性。
