Oncogenic functions and therapeutic targeting of EphA2 in cancer

Abstract

More than 25 years of research and preclinical validation have defined EphA2 receptor tyrosine kinase as a promising molecular target for clinical translation in cancer treatment. Molecular, genetic, biochemical, and pharmacological targeting strategies have been extensively tested in vitro and in vivo, and drugs like dasatinib, initially designed to target SRC family kinases, have been found to also target EphA2 activity. Other small molecules, therapeutic targeting antibodies, and peptide-drug conjugates are being tested, and more recently, approaches harnessing antitumor immunity against EphA2-expressing cancer cells have emerged as a promising strategy. This review will summarize preclinical studies supporting the oncogenic role of EphA2 in breast cancer, lung cancer, glioblastoma, and melanoma, while delineating the differing roles of canonical and noncanonical EphA2 signaling in each setting. This review also summarizes completed and ongoing clinical trials, highlighting the promise and challenges of targeting EphA2 in cancer.

Figure 1.. Eph Receptor Tyrosine Kinase Structure and Function.

A) Eph receptors bind to membrane bound ligands. Ephrin-A ligands, tethered to the membrane of adjacent cells by a GPI linkage, generally bind to Eph A class receptors, while Ephrin-B ligands, tethered by a transmembrane spanning domain, generally bind Eph B class receptors. This enables signaling through the receptor (forward signaling) and the ligand (reverse signaling). Upon activation by ligand, Eph receptors oligomerize and are autophosphorylated at juxtamembrane tyrosine residues. B) Noncanonical EphA2 signaling differs from canonical signaling in several ways. These mechanisms include signaling in the absence of ephrin ligand, heterodimerization of the EphA2 receptor with other RTKs such as ERBB2/HER2 or EGFR, and phosphorylation of serine 897 by AKT, RSK, or PKA. C) Key effects of oncogenic EphA2 signaling.

Figure 2.. EphA2 therapeutic targeting strategies.

Strategies to inhibit EphA2 in the clinic include EphA2-targeting antibody-cytotoxic drug conjugates (ADC) or peptide-drug conjugates (PDC), tyrosine kinase inhibitors (TKI) like dasatinib, CAR-T cells engineered to recognize and target EphA2 antigen, and nanocarriers designed to deliver siRNAs targeting EPHA2 to tumor cells. Potential future strategies for suppression of noncanonical signaling might also include canonical EphA2 agonists such as soluble ephrin-A1 (A1-Fc), or other small-molecule inhibitors to block EphA2 phosphorylation at S897 (AKTi/RSKi/PKAi).