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Critical role of EphA3 in cancer and current state of EphA3 drug therapeutics

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Abstract

The erythropoietin-producing human hepatocellular (Eph) receptors are transmembrane glycoprotein members of the tyrosine kinase receptors family. The Ephs may bind to various ephrin ligands resulting in the phosphorylation of their tyrosine kinase domain and the activation of the Eph receptor. In this review we focus on EphA3, one receptor of the 14 different Ephs, as it carries out both redundant and restricted functions in the germline development of mammals and in the maintenance of various adult tissues. The loss of EphA3 regulation is correlated with various human malignancies, the most notable being cancer. This receptor is overexpressed and/or mutated in multiple tumors, and is also associated with poor prognosis and decreased survival in patients. Here we highlight the role of EphA3 in normal and malignant tissues that are specific to cancer; these include hematologic disorders, gastric cancer, glioblastoma multiforme, colorectal cancer, lung cancer, renal cell carcinoma, and prostate cancer. Moreover, various anticancer agents against EphA3 have been developed to either inhibit its kinase domain activity or to function as agonists. Thus, we examine the most potent small molecule drugs and mAb-based therapeutics against EphA3 that are currently in pre-clinical or clinical stages.

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Abbreviations

EGF:

Epidermal growth factor

RTKs:

Receptor tyrosine kinases

LBD:

Ligand binding domain

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

NSCLC:

Non-small cell lung cancer

SCLC:

Small-cell lung cancer

ccRCC:

Clear-cell renal cell carcinoma

MAPK:

Mitogen-activated protein kinase

PCa:

Prostate cancer

AR:

Androgen receptor

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Acknowledgements

This work was partially supported by the Charles H. Best foundation (EG).

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    Max London & Eugenio Gallo

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London, M., Gallo, E. Critical role of EphA3 in cancer and current state of EphA3 drug therapeutics. Mol Biol Rep 47, 5523–5533 (2020). https://doi.org/10.1007/s11033-020-05571-8

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