Inhibition of EGFR via an acidity-responsive transmembrane peptide ligand.

Abstract

The epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinase (RTK) family of proteins that regulate cell migration, proliferation, and apoptosis. Mis-regulation of EGFR is a common cause of cancer, and therefore EGFR is often a target for anti-cancer therapeutics. However, current therapeutics are non-specific for cancerous over healthy tissue, as they target EGFR generally without considering its environment. Our lab has recently developed a new method for RTK inhibition that targets the acidic environment of tumors. The method utilizes a peptide which preferentially inserts to the plasma membrane in an acidic environment, and once inserted the peptide binds the transmembrane (TM) region of an RTK to allosterically regulate kinase activity. Here, we have applied this method to EGFR to create the PET1 peptide. PET1 directly interacts with EGFR to modify its TM dimer configuration. MD simulations reveal that the peptide sits between the EGFR TM dimer to inhibit native contacts. Based on an observed decrease in EGFR-mediated cell migration, we hypothesize that disruption of TM contacts changes the configuration of the kinase domain leading to inhibition. This study demonstrates not only that acidity-responsive membrane peptide ligands can be applied generally to RTKs, but also that TM-targeting is a viable therapeutic approach for EGFR inhibition.