Metformin-sensitized NSCLC cells to osimertinib via AMPK-dependent autophagy inhibition

Introduction The third-generation epidermal growth factor receptor (EGFR) inhibitor osimertinib is a promising therapeutic option for patients with advanced non-small-cell lung cancer (NSCLC) in second-line or first-line treatment because of its applications in selectively inhibiting EGFR T790M and EGFR-tyrosine kinase inhibitor sensitizing mutations. However, the activation of autophagy associated with osimertinib treatment may play a protective role in NSCLC cells injury induced by osimertinib. Objectives The aim of the present study was to study the effects of the osimertinib-induced autophagy in NSCLC cells and whether metformin modulates the autophagy and enhances osimertinib sensitivity. Methods The effect of metformin on enhancing osimertinib sensitivity was examined in vitro and in vivo using MTT, BrdUrd incorporation assay, colony formation assay, invasion assay, flow cytometry analysis, western blot analysis and siRNA technique. Results In the present study, we confirmed that osimertinib induced pro-survival autophagy in H1975 and PC-9GR cells, and metformin further sensitized H1975 and PC-9GR cells to osimertinib via inhibiting autophagy. The potential mechanism was that the continual activation of AMPK induced by metformin could inhibit autophagy in a time-dependent manner. Conclusion Metformin inhibited autophagy and enhanced osimertinib sensitivity via inducing AMPK activation in a time-dependent manner.