An Orally Available Grafted Peptide Targeting Epidermal Growth Factor Receptor Dimers Reduces Non-Small Cell Lung Cancer Tumors in Mouse Models

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.