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Targeting Epha2 in Cancer Ta Xiao1, Yuhang Xiao2, Wenxiang Wang3,4, Yan Yan Tang4, Zhiqiang Xiao2* and Min Su3,4*

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Targeting Epha2 in Cancer Ta Xiao1, Yuhang Xiao2, Wenxiang Wang3,4, Yan Yan Tang4, Zhiqiang Xiao2* and Min Su3,4* Xiao et al. Journal of Hematology & Oncology (2020) 13:114 https://doi.org/10.1186/s13045-020-00944-9 REVIEW Open Access Targeting EphA2 in cancer Ta Xiao1, Yuhang Xiao2, Wenxiang Wang3,4, Yan Yan Tang4, Zhiqiang Xiao2* and Min Su3,4* Abstract Eph receptors and the corresponding Eph receptor-interacting (ephrin) ligands jointly constitute a critical cell signaling network that has multiple functions. The tyrosine kinase EphA2, which belongs to the family of Eph receptors, is highly produced in tumor tissues, while found at relatively low levels in most normal adult tissues, indicating its potential application in cancer treatment. After 30 years of investigation, a large amount of data regarding EphA2 functions have been compiled. Meanwhile, several compounds targeting EphA2 have been evaluated and tested in clinical studies, albeit with limited clinical success. The present review briefly describes the contribution of EphA2-ephrin A1 signaling axis to carcinogenesis. In addition, the roles of EphA2 in resistance to molecular-targeted agents were examined. In particular, we focused on EphA2’s potential as a target for cancer treatment to provide insights into the application of EphA2 targeting in anticancer strategies. Overall, EphA2 represents a potential target for treating malignant tumors. Keywords: EphA2 receptor, Ephrin A1, Cancer, Therapy, Target Introduction ligand-binding and intrinsic enzymatic activities, respect- Ephrin receptors (Eph) represent the most important ively [7, 8]. Eph receptors are grouped into A and B class of receptor tyrosine kinases (RTKs) [1]. EphA1, the categories according to their extracellular domains, firstly described Eph receptor, was identified in liver which determine the binding affinity for ligands (Eph cancer cells while screening for RTKs in 1987 [2]. receptor-interacting proteins or ephrins) [9, 10]. Nine Nowadays, there are 14 Eph receptors and 8 related EphA and five EphB receptors are found in humans [11]. ligands (ephrins) [3]. Eph receptor signaling contributes The ligands for Eph receptors, ephrins, are anchored to to multiple biological events, mostly causing cell-cell the cell membrane; they also comprise two subcategor- repulsion or adhesion. Therefore, Eph receptors and the ies, including ephrin A (ephrin A1-5) and ephrin B corresponding ligands have essential functions in tissue (ephrin B1-3) [12, 13]. patterning, neuronal targeting, and blood vessel develop- Some Eph receptors, especially EphA2, attract increas- ment in the embryo [4, 5]. Meanwhile, Eph proteins are ing attention because of demonstrated or hypothesized found in high levels in multiple malignancies, with such contributions to modulatory processes controlling overexpression significantly contributing to carcinogen- carcinogenesis and tumor progression (Fig. 1). The esis [6]. present manuscript reviewed the clinical associations Eph receptors are single transmembrane proteins with and biological and cellular consequences of EphA2 extra- (N-terminal) and intracellular domains with overexpression in cancer. Potential opportunities for therapeutic intervention based on EphA2 targeting are particularly discussed. * Correspondence: [email protected]; [email protected] 2Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 3Thoracic Surgery Department 2, Hunan Cancer Hospital and The Affiliated EphA2-ephrin A1 signaling Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China The EphA2 receptor is a 130-kDa transmembrane glyco- Full list of author information is available at the end of the article protein with 976 amino acids [14]. The EphA2 gene in © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Xiao et al. Journal of Hematology & Oncology (2020) 13:114 Page 2 of 17 Fig. 1 Historical development and breakthroughs in targeting EphA2 in cancer humans is found on chromosome 1p36. Its initial detec- signaling by ephrin A1 is largely poorly understood. In tion occurred in 1990 while screening a HeLa cell cDNA addition, EphA2 possesses ligand-independent kinase ac- library comprising degenerate oligonucleotides engi- tivity in cultured cancer cells, which might partially ex- neered to interact with highly conserved domains of plain its malignant effects in the non-phosphorylated tyrosine kinases [12]. EphA2 was originally termed state [22, 23]. Actually, EphA2-ephrin A1 interaction or epithelial cell kinase (eck) since it was detected in most EphA2 ligand-independent kinase activity likely func- epithelial cells. tions through multiple factors acting jointly, e.g., cell EphA2 interacts with any of the eight different ephrin type and the microenvironment. Altogether, the EphA2- A-family ligands, with overt preference to ephrin A1 [13, ephrin A1 signaling regulates multiple cellular processes 15]. Ephrin A1 represents a GPI-anchored protein (proliferation, survival, migration, morphology, cell-to- containing 205 amino acids (apparent molecular weight, cell repulsion, and adhesion) in embryonic development, 22 kDa) [16]. The human ephrin A1 gene is located on angiogenesis, and tumorigenesis [11] (Fig. 2). 1q21-q22. This TNF-α early-inducible gene product was firstly described in human umbilical vein endothelial EphA2 in cancer cells (HUVECs) three decades ago [17], and shown to Different from the majority of Eph kinases that are bind EphA in 1994 [18]. Ephrin A1’s expression pattern mostly synthesized during the developmental process, in cancer seems to differ from that of EphA2, with at- EphA2 is mainly restricted to proliferating epithelial tenuation in a variety of aggressive tumors, particularly cells in adults [12]. EphA2 expression in the adult oc- those overexpressing EphA2 [16]. curs in normal tissues only when they have highly Under normal conditions, EphA2 interacts with ephrin proliferating epithelial cells [1], where its importance A1 on the neighboring cell and induce diverse signaling and function are not well understood. However, an networks following cell-to-cell contact. As membrane accumulating body of evidence suggests human proteins, ephrins are engaged in both forward (termed EphA2 is abundantly expressed in diverse cancers ephrin:EphA2 forward) and reverse (called EphA2:ephrin such as prostate [24], lung [25], esophageal [26], colo- reverse) signaling from ephrin ligands to EphA2 and vice rectal [27], cervical [28], ovarian [29], and breast [30] versa; this is also known as ephrin-EphA2 bidirectional and skin cancers [31]. EphA2 is upregulated at the signaling [19, 20]. Forward signaling is often cell gene and protein levels in human tumor tissue repulsive and promotes EphA2 oligomerization and specimens and established cancer cell lines [9, 16]. In phosphorylation, therefore enhancing kinase activity. particular, most elevated EphA2 expression is consist- The immediate biological consequences of EphA2 ently detected in cells with highest malignancy [16]. phosphorylation include decreased cell–extracellular In addition, EphA2 expression has associations with matrix (ECM) attachment. Ephrin A1-associated EphA2 poor prognosis, elevated metastatic potential, and re- induction inhibits focal adhesion kinase (FAK), extracel- duced survival of tumor patients [32, 33]. Moreover, lular regulated protein kinases (ERK), and Akt EphA2 is not simply a biomarker of malignant phosphorylation to regulate motility, viability, and prolif- character, but also an active participant in malignant eration in multiple malignant cell lines [7, 21], whereas progression [26, 28]. Consequently, EphA2’sexpres- reverse signaling is more likely to be adhesive and is sion patterns and functional relevance in malignancies generally considered as kinase-independent, due to lack- make this protein an attractive therapeutic target in ing enzyme activity in ephrin A1. However, the reverse cancer. Xiao et al. Journal of Hematology & Oncology (2020) 13:114 Page 3 of 17 Fig. 2 Expression and biological pathways linked with EphA2. The interaction of cell-membrane-bound EphA2 with ephrin A1 induces forward or reverse signals in the corresponding cells. Under normal conditions, cell–cell contacts allow EphA2 to interact with ephrin A1, which induces EphA2 phosphorylation and activates its downstream signaling. Tyrosine phosphorylation of EphA2 promotes the generation of a complex with c-Cbl, subsequently induces EphA2 degradation. This leads to suppression of ECM attachment, cell proliferation,
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