EGFR Targeted Liposomal PROTAC Assisted With Epigenetic Regulation as an Efficient Strategy for Osimertinib-Resistant...

Area of Science:

• Oncology
• Drug Delivery
• Molecular Biology

Background:

• Osimertinib resistance in non-small cell lung cancer (NSCLC) is a significant clinical challenge, driven by EGFR mutations and bypass pathways.
• Traditional Proteolysis Targeting Chimeras (PROTACs) face limitations in cell permeability and tumor targeting, hindering their efficacy against resistant lung cancer.
• Existing PROTACs often fail to address bypass resistance mechanisms effectively.

Purpose of the Study:

• To develop a versatile liposomal PROTAC platform for enhanced EGFR degradation in osimertinib-resistant NSCLC.
• To overcome the limitations of traditional PROTACs, including poor cell permeability and insufficient tumor targeting.
• To investigate the efficacy of a novel encapsulated drug (GM-protac) targeting both EGFR-dependent and bypass resistance pathways.

Main Methods:

• A split-and-mix liposomal PROTAC system was engineered using DSPE-PEG2000-E3 and DSPE-PEG2000-EGFR ligands for self-assembly.
• The liposomal PROTAC was encapsulated with the class I HDAC inhibitor MS-275, creating GM-protac.
• GM-protac's efficacy, toxicity, and mechanism of action were evaluated in resistant lung cancer cell lines and animal models.

Main Results:

• The liposomal PROTAC demonstrated efficient EGFR degradation through both E3-dependent and lysosome-autophagy pathways.
• GM-protac exhibited selective toxicity towards gefitinib- and osimertinib-resistant lung cancer cells.
• Mechanism analysis indicated GM-protac influences key signaling pathways including BIM-associated apoptosis, c-Met, PD-L1, HER-2, NF-κB, and PI3K-AKT.
• GM-protac achieved significant tumor inhibition with negligible toxicity in resistant lung cancer xenograft models.

Conclusions:

• The developed liposomal PROTAC platform offers an effective strategy for overcoming osimertinib resistance in NSCLC.
• GM-protac represents a promising therapeutic candidate by simultaneously targeting EGFR-dependent pathways and bypass mechanisms.
• This approach provides a potential new treatment option for patients with resistant non-small cell lung cancer.