The EphA2 and cancer connection: potential for immune-based interventions
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REVIEW
The EphA2 and cancer connection: potential for immune‑based interventions Max London1 · Eugenio Gallo1 Received: 31 May 2020 / Accepted: 28 August 2020 © Springer Nature B.V. 2020
Abstract The Eph (erythropoietin-producing human hepatocellular) receptors form the largest known subfamily of receptor tyrosine kinases. These receptors interact with membrane-bound ephrin ligands via direct cell–cell interactions resulting in bi-directional activation of signal pathways. Importantly, the Eph receptors play critical roles in embryonic tissue organization and homeostasis, and in the maintenance of adult processes such as long-term potentiation, angiogenesis, and stem cell differentiation. The Eph receptors also display properties of both tumor promoters and suppressors depending on the cellular context. Characterization of EphA2 receptor in regard to EphA2 dysregulation has revealed associations with various pathological processes, especially cancer. The analysis of various tumor types generally identify EphA2 receptor as overexpressed and/or mutated, and for certain types of cancers EphA2 is linked with poor prognosis and decreased patient survival. Thus, here we highlight the role of EphA2 in malignant tissues that are specific to cancer; these include glioblastoma multiforme, prostate cancer, ovarian and uterine cancers, gastric carcinoma, melanoma, and breast cancer. Due to its large extracellular domain, therapeutic targeting of EphA2 with monoclonal antibodies (mAbs), which may function as inhibitors of ligand activation or as molecular agonists, has been an oft-attempted strategy. Therefore, we review the most current mAb-based therapies against EphA2 expressing cancers currently in pre-clinical and/or clinical stages. Finally, we discuss the latest peptides and cyclical-peptides that function as selective agonists for EphA2 receptor. Keywords Receptor tyrosine kinase · Antibody therapeutics · EphA2 receptor · Erythropoietin-producing hepatocellular receptor · Oncology · Cancer therapeutics Abbreviations RTKs Receptor tyrosine kinases LBD Ligand binding domain MAPK Mitogen-activated protein kinase mAb Monoclonal antibody Eph Erythropoietin-producing hepatocellular ECD Extracellular domain FN3 Fibronectin type-III JxM Juxtamembrane SAM Sterile alpha-motif Ephrins Eph receptor-interacting proteins GBM Glioblastoma multiforme * Eugenio Gallo [email protected] Max London [email protected] 1
Department of Molecular Genetics, University of Toronto, Donnelly Centre, 160 College Street, Toronto, ON M5S 3E1, Canada
TPCs Tumor progenitor cells TNM Tumor-node-metastasis YAP Yes‐associated protein EMT Epithelial-to-mesenchymal transition BiTE Bispecific T-cell engager molecule ADCC Antibody-dependent cellular cytotoxicity NK Natural killer SCID Severe compromised immunodeficient NOD Nonobese diabetic MMAF Monomethyl auristin phenylalanine
Introduction The largest sub-family of receptor tyrosine kinases (RTKs) is composed of the erythropoietin-producing hepatocellular (Eph) rec
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