Epidermal Growth Factor Receptor and Eph Receptor A2: Understanding mechanisms of activation and therapeutic resistance of receptor tyrosine kinases

Receptor tyrosine kinases (RTKs) are an essential class of membrane proteins that translate extracellular signals to the intracellular space. Dysregulation of RTKs commonly results in cancer, and continued investigation of the activation and signaling mechanisms of RTKs is essential to the development of new anti-cancer therapeutics. This work focuses primarily on two RTKs, the epidermal growth factor receptor (EGFR) and the Eph family type A2 receptor (EphA2). Individually, these RTKs are interesting therapeutic targets, but there is also evidence that the interaction between these proteins is responsible the development of tumor resistance to EGFR-targeting therapies. We first develop a novel peptide inhibitor of EGFR that functions by binding the transmembrane domain, an uncommon method for RTK inhibition (Chapter II). We then further investigate the basic mechanisms of EGFR-EphA2 interactions. We test novel styrene maleic acid copolymer derivatives for the ability to co-solubilize EGFR and EphA2 (Chapter III). We then understand the effects of the negatively-charged lipid PIP2 (Chapter IV) and ligand-directed endocytosis (Chapter V) on the EGFR-EphA2 interaction. Finally, we begin to understand how glycosylation of EphA2 regulates the receptor’s activity with the end goal of determining how EGFR modulates EphA2 glycosylation (Chapter VI). Collectively, these findings contribute to basic knowledge of EGFR-EphA2 interaction mechanisms, which will inform RTK pharmaceutical development in cancer.