Autophagy determines osimertinib resistance through regulation of stem cell-like properties in EGFR-mutant lung cancer

Drug resistance to Osimertinib, a 3rd-generation EGFR-TKI is inevitable. Autophagy plays a contradictory role in resistance of 1st and 2nd generation EGFR-TKI, and its significance in osimertinib resistance is much less clear. We therefore investigated whether autophagy determines osimertinib resistance. First, osimertinib induced autophagy to a much greater extent than that of gefitinib, and autophagy inhibition further increased osimertinib efficacy. Next, enhanced autophagy was found in osimertinib resistant cells and autophagy inhibition partially reversed osimertinib resistance. Enhanced stem-cell like properties were found in resistant cells, and siRNA-knock down of SOX2 or ALDH1A1reversed osimertinib resistance. Of note, autophagy inhibition or siRNA-knock down of Beclin-1 decreased expression of SOX2 and ALDH1A1 and stem-cell like properties. Next, autophagy inhibition and osimertinib in combination effectively blocked tumor growth in xenografts, which was associated with decreased autophagy and stem cell-like properties in vivo. Finally, enhanced autophagy was found in lung cancer patients with resistance to osimertinib. In conclusion, the current study delineates a previously unknown function of autophagy in determining osimertinib resistance through promoting stem-cell like properties.