Development of Targeted EGFR Degradation for Cancer Treatment

Abstract

Chemotherapeutic interruption of signaling pathways at receptor tyrosine kinases is an important strategy for attenuating cancer progression. We have synthesized a new generation of polyfunctionalized heterocyclic compounds that bind to an allosteric site in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). The bound compounds induce degradation of the receptor by endocytosis in cancer cells. The Hsp90α chaperone binds to EGFR and is significantly lost during endocytosis, thereby contributing to the reduction of client proteins. Induced EGFR depletion leads to inactivation of downstream signaling due to sequestration of the Bim sensor protein for cytoskeletal proteins, provoking cell detachment from the extracellular matrix and ultimately cancer cell death. The role of glutamine in maintaining the phosphorylation status of EGFR-mediated signaling pathways can be postulated as «no glutamine, no EGFR signaling». Targeted degradation of EGFR is attractive for aiming to attenuate metastatic progression and to override the drug resistance of malignant tumors.