American Association for Cancer Research
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Supplement Figure 3 from Auranofin Enhances Ibrutinib's Anticancer Activity in EGFR-Mutant Lung Adenocarcinoma

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posted on 2023-04-03, 15:04 authored by Jing Hu, Huijuan Zhang, Mengru Cao, Li Wang, Shuhong Wu, Bingliang Fang

Relative value of phosphor-AKT, mTOR, 70S6K, MEK and ERK based on intensity of Western blot bands of Figure 4. Up panel: H1975; low panel: H1650. The value was determined using software ImageJ and normalized with β-actin.


National Science Fund Youth of Fund of China

60th Postdoctoral Natural Science Fund of China

7th Postdoctoral Special Science-Research Fund of Heilongjiang Province

Haiyan Fund of Harbin Medical University Cancer Hospital grant

National Institutes of Health

University of Texas MD Anderson Cancer Center support grant



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 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. Mol Cancer Ther; 17(10); 2156–63. ©2018 AACR.

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