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Review
.2011 Jan;15(1):31-51.
doi: 10.1517/14728222.2011.538682.

Emerging strategies for EphA2 receptor targeting for cancer therapeutics

Affiliations
Review

Emerging strategies for EphA2 receptor targeting for cancer therapeutics

Manish Tandon et al. Expert Opin Ther Targets.2011 Jan.

Abstract

Importance of the field: High mortality rates with cancers warrant further development of earlier diagnostics and better treatment strategies. Membrane-bound erythropoietin-producing hepatocellular receptor tyrosine kinase class A2 (EphA2) is overexpressed in breast, prostate, urinary bladder, skin, lung, ovary and brain cancers.

Areas covered in this review: EphA2 overexpression in cancers, its signaling mechanisms and strategies to target its deregulation.

What the reader will gain: High EphA2 expression in cancer cells is correlated with a poor prognosis associated with recurrence due to enhanced metastasis. Interaction of the EphA2 receptor with its ligand (e.g., ephrinA1) triggers events that are deregulated and implicated in carcinogenesis. EphrinA1-independent oncogenic activity and ephrinA1-dependent tumor suppressor roles for EphA2 are described. Molecular interactions of EphA2 with signaling proteins are associated with the modulation of cytoskeleton dynamics, cell adhesion, proliferation, differentiation and metastasis. The deregulated signaling by EphA2 and its involvement in oncogenesis provide multiple avenues for the rational design of intervention approaches.

Take home message: EphA2 has been tested as a drug target using multiple approaches such as agonist antibodies, RNA interference, immunotherapy, virus vector-mediated gene transfer, small-molecule inhibitors and nanoparticles. With over a decade of research, encouraging results with targeting of EphA2 expression in various pre-clinical cancer models necessitate further studies.

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Conflict of interest statement

Declaration of Interest

This work was supported by Public Health Service grant CA110176 from the National Cancer Institute.

The authors declare no other conflict of interest.

Figures

Figure 1
Figure 1. EphA2 and EphrinA1 signaling in cancers
EphA2 receptor tyrosine kinase and its ligand EphrinA1 belong to the Eph family of receptors. The interaction of cell membrane bound EphA2 with EphrinA1 generates forward or reverse signals in the corresponding cells. The cell-cell contact-dependent functioning of Eph receptors and Ephrins is tightly regulated during normal embryonic development and maintenance of homeostasis. However, during oncogenesis due to loss of cell contacts, the normal EphA2-EphrinA1 signaling is disrupted leading to the overexpression of EphA2 and oncogenic signal transduction. This deregulated signaling is implicated in several critical aspects of oncogenesis such as cytoskeleton modulation, cell adhesion, migration, metastasis, proliferation and angiogenesis.
Figure 2
Figure 2. The role of EphA2 in the normal versus the cancer cell
EphA2 is present on the surface of a normal cell and interacts with its ligand (e.g., EphrinA1) which is present on the surface of adjacent cells. Upon interaction, EphA2 becomes phosphorylated and subsequently degraded. The phosphorylation of EphA2 is important for the normal signaling of MAPK and Akt pathways. In cancer cells, EphA2 fails to efficiently interact with its ligand on adjacent cells, leading to the accumulation of the unphosphorylated-form of EphA2 in the cell. This leads to oncogenic signaling; however, the underlining mechanism/s is/are not clear. MAPK, mitogen activated protein kinases; Akt, associated protein kinase B; ↔, interaction; X, no interaction.
Figure 3
Figure 3. Targeting EphA2 in breast cancer
EphA2 receptor tyrosine kinase is reported to regulate multiple aspects of oncogenesis such as cell survival, cytoskeleton modulation, cell adhesion, tumor-associated angiogenesis and metastasis. The deregulated signaling by EphA2 receptor provides multiple avenues to design rational intervention approaches. Accordingly, EphA2 overexpression has been targeted with several approaches such as agonist antibodies, small molecule inhibitors, viral vectors, RNA-interference, cancer immunotherapy and combination of these therapeutic approaches.
Figure 4
Figure 4. Simplified view of the development of EphA2 as a target for cancer therapeutics
The identification of a differential expression pattern and mechanisms of EphA2 in normalversus cancer cells by severalin vitro techniques (highlighted in yellow) have led to the pre-clinical testing in mouse models of cancers (highlighted in green). After the validation of pre-clinical data and ensuring the safety of various therapeutic strategies, multiple stages of clinical trials and a review process need to be conducted (highlighted in orange) to develop EphA2-targeting anti-cancer therapeutics.
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