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Review

EphA2 in Cancer: Molecular Complexity and Therapeutic Opportunities

by
Lisa Toracchio
1,†,
Marianna Carrabotta
1,†,
Caterina Mancarella
1,
Andrea Morrione
2 and
Katia Scotlandi
1,*
1
Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
2
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2024, 25(22), 12191; https://doi.org/10.3390/ijms252212191
Submission received: 8 October 2024 / Revised: 7 November 2024 / Accepted: 11 November 2024 / Published: 13 November 2024
(This article belongs to the Special Issue Molecular Insight into Cell Signalling Proteins)

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

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MDPI and ACS Style

Toracchio, L.; Carrabotta, M.; Mancarella, C.; Morrione, A.; Scotlandi, K. EphA2 in Cancer: Molecular Complexity and Therapeutic Opportunities. Int. J. Mol. Sci. 2024, 25, 12191. https://doi.org/10.3390/ijms252212191

AMA Style

Toracchio L, Carrabotta M, Mancarella C, Morrione A, Scotlandi K. EphA2 in Cancer: Molecular Complexity and Therapeutic Opportunities. International Journal of Molecular Sciences. 2024; 25(22):12191. https://doi.org/10.3390/ijms252212191

Chicago/Turabian Style

Toracchio, Lisa, Marianna Carrabotta, Caterina Mancarella, Andrea Morrione, and Katia Scotlandi. 2024. "EphA2 in Cancer: Molecular Complexity and Therapeutic Opportunities" International Journal of Molecular Sciences 25, no. 22: 12191. https://doi.org/10.3390/ijms252212191

APA Style

Toracchio, L., Carrabotta, M., Mancarella, C., Morrione, A., & Scotlandi, K. (2024). EphA2 in Cancer: Molecular Complexity and Therapeutic Opportunities. International Journal of Molecular Sciences, 25(22), 12191. https://doi.org/10.3390/ijms252212191

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