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An Orally Available Grafted Peptide Targeting Epidermal Growth Factor Receptor Dimers Reduces Non-Small Cell Lung
Prajesh Shrestha1,2, Sitanshu S Singh2, Achyut Dahal2
1Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, United States.
Abstract:
Epidermal growth factor receptors, such as human epidermal growth factor receptors (EGFR, HER1) and HER2, HER3, are essential in cell growth and differentiation. EGFR, HER2, and HER3 dimerize to generate signaling for cell growth, and in cancer cells, these receptors are either overexpressed or harbor mutations, resulting in uncontrolled signaling. The dimerization of these receptors is required for signaling and can be inhibited by peptides and antibodies. We have designed a grafted peptide, SFTI-G5, that targets the HER2 protein and inhibits dimerization of both EGFR:HER2 and HER2:HER3. To develop the grafted peptide as an orally bioavailable peptide, we evaluated the stability of the peptide against enzymatic degradation. Oral administration of SFTI-G5 at 50 mg/kg suppressed the growth of lung cancer cell lines that overexpress the HER2 protein in a mouse xenograft model. To evaluate the specificity of the peptide for the HER2 protein, a patient-derived xenograft (PDX) model of mice with low HER2 expression was used. The peptide did not have any effect on tumor growth in the low HER2 expression model, suggesting the specificity of the peptide for the HER2 protein. Pharmacokinetic studies via the IV route indicated that the peptide is stable in serum, with a terminal half-life of more than 40 h. These studies suggest that stable grafted cyclic peptides can be designed to target protein-protein interactions and that these peptides can be made orally bioavailable.
Insights
A novel peptide, SFTI-G5, effectively inhibits human epidermal growth factor receptor (EGFR) dimerization, suppressing lung cancer growth. This peptide shows promise for oral bioavailability and targeted cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Epidermal growth factor receptors (EGFR, HER1, HER2, HER3) are crucial for cell growth but are implicated in uncontrolled cancer signaling when overexpressed or mutated.
- Receptor dimerization is essential for signaling, presenting a therapeutic target for cancer treatment.
Purpose of the Study:
- To design and evaluate a novel grafted peptide, SFTI-G5, targeting HER2 to inhibit EGFR:HER2 and HER2:HER3 dimerization.
- To assess the oral bioavailability and stability of SFTI-G5 for potential cancer therapy.
Main Methods:
- Designed a grafted peptide (SFTI-G5) targeting HER2.
- Evaluated peptide stability against enzymatic degradation.
- Assessed SFTI-G5 efficacy in a HER2-overexpressing lung cancer xenograft mouse model.
- Tested peptide specificity using a low HER2 expression patient-derived xenograft (PDX) model.
- Conducted pharmacokinetic studies to determine serum stability and half-life.
Main Results:
- SFTI-G5 successfully inhibited EGFR:HER2 and HER2:HER3 dimerization.
- Oral administration of SFTI-G5 suppressed tumor growth in HER2-positive lung cancer models.
- The peptide demonstrated specificity for HER2, with no effect in low HER2 expression models.
- SFTI-G5 exhibited stability in serum with a terminal half-life exceeding 40 hours.
Conclusions:
- Stable grafted cyclic peptides can be designed to target protein-protein interactions, specifically HER2 dimerization.
- SFTI-G5 shows potential as an orally bioavailable therapeutic agent for HER2-driven cancers.
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