Synergistic Targeting HER2 and EGFR with Bivalent Aptamer-siRNA Chimera Efficiently Inhibits HER2-Positive Tumor...

Area of Science:

• Oncology
• Molecular Biology
• Biotechnology

Background:

• HER2 overexpression occurs in 20-30% of breast and other cancers.
• Current HER2-targeted therapies face limitations due to drug resistance and toxicity.
• EGFR upregulation is linked to resistance in HER2-targeted drug treatments.

Purpose of the Study:

• To develop a novel nucleic acid therapeutic targeting both HER2 and EGFR.
• To overcome limitations of current HER2-targeted drugs, including resistance and toxicity.
• To evaluate the efficacy of the bivalent HER2 aptamer-EGFR siRNA aptamer chimera (HEH) in preclinical models.

Main Methods:

• Constructed a bivalent HER2 aptamer-EGFR siRNA aptamer chimera (HEH).
• Tested HEH's cellular uptake and gene silencing in HER2-expressing breast cancer cell lines.
• Assessed HEH's anti-tumor efficacy, including apoptosis induction and gene expression modulation, in breast cancer xenograft models.

Main Results:

• HEH selectively targets and is internalized by HER2-expressing cancer cells.
• HEH effectively silences the EGFR gene and downregulates HER2 expression.
• In vivo studies showed HEH suppresses tumor growth, induces apoptosis, and reduces HER2/EGFR expression, outperforming HER2 aptamer alone.

Conclusions:

• HEH demonstrates synergistic effects by co-targeting HER2 and EGFR.
• HEH exhibits superior therapeutic efficacy compared to HER2 aptamer monotherapy.
• HEH shows significant potential as a novel therapeutic agent for HER2-positive cancers, addressing current drug limitations.