EphA2 in Cancer: Molecular Complexity and Therapeutic Opportunities

Abstract

Erythropoietin-producing hepatocellular A2 (EphA2) is a member of the Eph tyrosine kinase receptor family that has been linked to various biological processes. In tumors, EphA2 overexpression is associated with noncanonical pathway activation, tumor progression, and a poor prognosis, which has emphasized its importance as a marker of malignancy. Studies on numerous cancer models have highlighted EphA2's dual and often contradictory action, which can be attributed to EphA2's interactions involving multiple pathways and different ligands, as well as the heterogeneity of the tumor microenvironment. In this review, we summarize the main mechanisms underlying EphA2 dysregulation in cancer, highlighting its molecular complexity. Then, we analyze therapies that have been developed over time to counteract its action. We discuss the limitations of the described approaches, emphasizing the fact that the goal of new options is high specificity without losing therapeutic efficacy. For this reason, immunotherapy or the emerging field of targeted protein degradation with proteolysis-targeting chimeras (PROTACs) may represent a promising solution that can be developed based on a deeper understanding of the molecular mechanisms sustaining EphA2 oncogenic activity.

Keywords: EphA2; cancer hallmarks; immunotherapy; nucleic-acid-based therapy; protein degradation; small molecule inhibitors; targeted therapy.

Figure 1

Schematic representation of EphA2-driven mechanisms in cancer. (A) In tumor cells, EphA2 predominantly acts through ligand-independent signaling and phosphorylation of the intracellular S897 residue by kinases that support proliferative and promigratory pathways. (B) An exception is the mechanism triggered by the interaction of EphA2 with progranulin, where this alternative ligand evokes EphA2 phosphorylation on S897 mediated prevalently by Erk1/2 and, to a lesser extent, AKT activation, driving a feedback mechanism on the receptor. (C) Ligand-independent homotypic head–tail (HT) interactions between the amino-terminal portion of EphA2 and the membrane-proximal domain of a neighboring receptor led to S897 activation and tumor progression. Panels (D,E) show two different ways to activate ligand-independent signaling. (D) The drawing illustrates the endocytosis of the ligand–receptor complex, followed by degradation. Alterations in the UPS/c-Cbl system are responsible for an imbalance in degradation mechanisms of EphA2, resulting in the accumulation of the receptor at the plasma membrane and the formation of clusters, which facilitates ligand-independent receptor activation. (E) EphA2 cleavage and processing by metalloproteases is a mechanism by which cancer cells can escape ligand-dependent tumor-suppressive signaling. Created using BioRender.

Figure 2

Schematic representation of EphA2 inhibition versus degradation approaches in cancer. Tyrosine kinase inhibitors, small molecules, or monoclonal antibodies inhibit EphA2 either by mimicking the action of ephrin A1 ligands and activating canonical signaling, or by inhibiting the kinase domain. mAbs can be also conjugated to drugs or toxins that target the internalization and degradation of the receptor. PROTACs are next-generation constructs that respond to the demand for greater specificity in receptor recognition. Their action is driven by linker molecules and the ubiquitin system, which trigger targeted protein degradation, resulting in the inhibition of cell growth, migration, and invasion. Created using BioRender.

Figure 3

Schematic representation of bicycle peptides, nanoparticles- or immunotherapy-based therapeutic strategies targeting EphA2. Bicycle peptides can deliver toxic conjugates, while nanoparticles can be a useful strategy for delivering drugs or siRNAs directly to tumor cells with high EphA2 expression. Nanoliposomes carrying siRNAs against EphA2 downregulate receptor expression. Conversely, peptide-conjugated nanoliposomes targeting EphA2 exploit the presence of the receptor on tumor cells to allow the direct and specific internalization of drugs in cells with high EphA2 expression only. In immunotherapy, two approaches can be used: recruitment of killer cells by T cells engineered to recognize tumor cells expressing EphA2, or CAR-T cells, with the common goal of inducing tumor cell death. Created using BioRender.