Nrf2 Inhibitor, Brusatol in Combination with Trastuzumab Exerts Synergistic Antitumor Activity in HER2-Positive Cancers by Inhibiting Nrf2/HO-1 and HER2-AKT/ERK1/2 Pathways.

The HER2-targeting antibody trastuzumab has shown effectiveness in treating HER2-positive breast and gastric cancers; however, its responses are limited. Currently, Nrf2 has been deemed as a key transcription factor in promoting cancer progression and resistance by crosstalk with other proliferative signaling pathways. Brusatol as a novel Nrf2 inhibitor has been deemed as an efficacious and safe drug candidate in cancer therapy. In this study, we firstly reported that brusatol exerted the growth-inhibitory effects on HER2-positive cancer cells by regressing Nrf2/HO-1 and HER2-AKT/ERK1/2 signaling pathways in these cells. More importantly, we found that brusatol synergistically enhanced the antitumor activity of trastuzumab against HER2-positive SK-OV-3 and BT-474 cells, which may be attributed to the inhibition of Nrf2/HO-1 and HER2-AKT/ERK1/2 signaling pathways. Furthermore, the synergistic effects were also observed in BT-474 and SK-OV-3 tumor xenografts. In addition, our results showed that trastuzumab markedly enhanced brusatol-induced ROS accumulation and apoptosis level, which could further explain the synergistic effects. To conclude, the study provided a new insight on exploring Nrf2 inhibition in combination with HER2-targeted trastuzumab as a potential clinical treatment regimen in treating HER2-positive cancers.