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EGFR Targeted Liposomal PROTAC Assisted With Epigenetic Regulation as an Efficient Strategy for Osimertinib-Resistant
Dongyuan Wang1,2, Yajing Liu1,2, Ying Chen3,4
1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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.
Insights
A novel liposomal proteolysis targeting chimera (PROTAC) drug, GM-protac, effectively degrades mutant EGFR in lung cancer cells resistant to osimertinib. This approach targets both EGFR-dependent and bypass resistance mechanisms, showing significant tumor inhibition with minimal toxicity in preclinical models.
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.
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