Effective Degradation of Wild-Type and Mutant EGFR Using Self-Assembling Peptide-Derived PROTAC Nanoparticles...

Area of Science:

• Nanotechnology in Cancer Therapy
• Molecular Targeted Therapy
• Drug Delivery Systems

Background:

• Epidermal growth factor receptor (EGFR)-targeted therapies like monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) face limitations due to drug resistance and off-target toxicity.
• There is a critical need for novel therapeutic strategies to overcome these limitations and effectively target both wild-type and mutant EGFR in heterogeneous cancers.

Purpose of the Study:

• To develop and evaluate self-assembling peptide-derived PROTAC nanoparticles (NanoTACs) for the targeted degradation of wild-type and mutant EGFR in cancer therapy.
• To assess the efficacy, tumor-targeting efficiency, and safety profile of NanoTACs in preclinical cancer models.

Main Methods:

• Construction of NanoTACs using three peptide components: an EGFR-binding peptide, a self-assembling peptide linker, and an E3 ligase recruiting peptide.
• Characterization of nanoparticle formation and size under aqueous conditions.
• In vitro evaluation of EGFR degradation in cancer cells via lysosomal and proteasomal pathways.
• In vivo assessment of tumor-targeting efficiency, tumor growth suppression, EGFR degradation, apoptosis induction, and systemic toxicity in colon and lung tumor models.

Main Results:

• Self-assembling peptide-derived PROTACs formed uniform spherical nanoparticles (average diameter 144 nm).
• NanoTACs effectively degraded both wild-type and L858R/T790M-mutant EGFR in cancer cells in vitro.
• In vivo studies demonstrated enhanced tumor-targeting efficiency (2.24-fold higher), significant tumor growth suppression (88.3%), high EGFR degradation (95% wild-type, 80% mutant), and extensive apoptosis induction without systemic toxicity.

Conclusions:

• NanoTACs represent a promising new platform for EGFR-targeted cancer therapy, capable of degrading both wild-type and mutant forms of the receptor.
• This approach effectively overcomes resistance mechanisms associated with traditional mAbs and TKIs.
• NanoTACs offer a potential strategy for treating heterogeneous cancers with improved efficacy and safety.