Pantoprazole enhances osimertinib activity by inhibiting autophagy in NSCLC cells and tumor xenografts

Abstract Here we examined whether Osimertinib (OSI) resistance which due to induced autophagy could be reversed by inhibiting autophagy with Pantoprazole. The effects of OSI ± pantoprazole were examined in four different non-small-cell lung cancer (NSCLC) cell lines, along with two human xenograft models. The effects of OSI ± pantoprazole on autophagy and drug effects were evaluated. Alterations in PI3K/Akt/mTOR pathway activation were also evaluated. Combination of OSI and pantoprazole resulted in decreased proliferation and tumor inhibition in NSCLC cells compared to single agent therapy. Treatment with OSI alone resulted in up-regulation of autophagy in NSCLC cells. Pantoprazole inhibited the induction of autophagy and sensitized NSCLC cells to OSI. When used together, OSI and pantoprazole increased apoptosis and reactive oxygen species (ROS) generation in NSCLC cells. Pantoprazole effectively reversed OSI-mediated suppression of the PI3K/Akt/mTOR pathway in NSCLC cells. Pharmacological autophagy inhibition sensitized NSCLC cells to OSI and enhanced the efficacy of OSI.