EGFR Targeted Liposomal PROTAC Assisted With Epigenetic Regulation as an Efficient Strategy for Osimertinib‐Resistant Lung Cancer Therapy

Abstract Osimertinib resistance is a global problem for NSCLC patients mediated by new EGFR mutations or bypass mechanisms. Proteolysis targeting chimeras (PROTACs) have been utilized to overcome drug resistance by degrading mutant EGFR, but most are restricted to their poor cell permeability and insufficient tumor‐targeting ability. Meanwhile, these PROTACs has little effect on bypass resistance mechanisms. In this study, a versatile split‐and‐mix liposomal PROTAC is developed for EGFR degradation based on liposome self‐assembly containing DSPE‐PEG2000‐E3 ligand and DSPE‐PEG2000‐EGFR ligand. Unlike traditional PROTACs, this platform can achieve efficient EGFR degradation via both E3‐dependent mechanisms and the lysosome‐autophagy pathway. To further increase its sensitivity to osimertinib‐resistant lung cancer cells, the liposomal PROTAC is encapsulated with class I HDAC inhibitor MS‐275 (GM‐protac) by both blocking the EGFR‐dependent pathways and bypass resistant mechanisms. GM‐protac shows selective toxicity on gefitinib‐resistant and osimertinib‐resistant lung cancer cells. The mechanism analysis reveals that GM‐protac can influence the BIM‐associated apoptosis pathway, c‐Met, PD‐L1, HER‐2, NF‐κB or PI3K‐AKT signaling pathway, etc. Meanwhile, they displayed obvious tumor inhibition with negligible toxicity in both osimertinib and gefitinib‐resistant lung cancer animal models. This work provides an alternative option for osimertinib‐resistant lung cancer therapy.