Shikonin sensitizes wild‑type EGFR NSCLC cells to erlotinib and gefitinib therapy.

As patients with non‑small cell lung cancer (NSCLC) and wild‑type epidermal growth factor receptor (EGFR) are resistant to treatment with erlotinib or gefitinib, potential chemosensitizers are required to potentiate wild‑type EGFR NSCLC cells to erlotinib/gefitinib treatment. The present study reported that shikonin could sensitize the anticancer activity of erlotinib/gefitinib in wild‑type EGFR NSCLC cells. Furthermore, shikonin could potentiate mitochondrial‑mediated apoptosis induced by erlotinib/gefitinib in wild‑type EGFR NSCLC cells. In addition, the present study demonstrated that shikonin could induce apoptosis by activating reactive oxygen species (ROS)‑mediated endoplasmic reticulum (ER) stress, and that erlotinib/gefitinib may also induce ER stress in wild‑type EGFR NSCLC cells; however, shikonin plus erlotinib/gefitinib was more effective in activating ER stress than either agent alone. This indicated that ROS‑mediated ER stress may be associated with enhanced mitochondrial apoptosis induced by shikonin plus erlotinib/gefitinib. In addition, shikonin may promote the transition of cytoprotective ER stress‑inducing EGFR‑tyrosine kinase inhibitor tolerance to apoptosis‑promoting ER stress. Furthermore, shikonin may enhance the anti‑NSCLC activity of erlotinib/gefitinib in vivo. The data of the present study indicated that shikonin may be a potential sensitizer to enhance the anti‑cancer efficacy of erlotinib/gefitinib in wild‑type EGFR NSCLC cells resistant to erlotinib/gefitinib treatment.