Abstract 3240: Designer peptides targeting epidermal growth factor as novel anti-breast cancer agents

Abstract

Abstract Triple negative breast cancer (TBNC) is the only major type of breast cancer for which no specific FDA approved target therapy is available to improve patient outcomes. TNBC lacks the usual breast cancer targets estrogen receptor (ER), progesterone receptor (PR) and HER2/neu receptor. Studies have shown that TBNC does express the epidermal growth factor receptor and has recently emerged as one of the potential targets in TBNC. Epidermal growth factor (EGF) mediates several cellular functions and processes such as survival, motility, differentiation, proliferation and death. When it is released by epidermal tissues, EGF binds to cell surface receptors such as the Epidermal growth factor receptor (EGFR) causing a conformational change which facilitates its dimerization. This receptor dimerization triggers its tyrosine kinase-mediated signal transduction activity. Apart from EGF, EGFR is reported to bind to Transforming growth factor alpha (TGF-α), Argos and Potato Carboxypeptidase inhibitor (PCI). All of these proteins have unique structural motifs which targets EGFR. PCI’s structure consisting of three disulfide bridges presents a unique knot like binding motif resembling EGF and is able to compete with EGF for its binding site on EGFR preventing receptor dimerization thereby antagonizing its action. We have used an integrated computational drug discovery approach to generate several PCI derived peptidic ligands targeting EGFR protein-protein interactions. PCI- peptides bind to EGFR in silico and block EGFR-mediated cell growth, proliferation and migration in vitro. We believe these designer peptidic inhibitors will provide structural and mechanistic clues towards novel therapeutics to combat TNBC. Citation Format: Emmanuel Yawson, Angel Garcia, Husamuldeen Dhari, Rajendram V. Rajnarayanan. Designer peptides targeting epidermal growth factor as novel anti-breast cancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3240. doi:10.1158/1538-7445.AM2017-3240