Cancer treatment target: EphA2

▲TG-Bio has joined hands with more than 600 industry colleagues and will open in April ▲Adrenergic receptor (Eph) is a very important type of receptor tyrosine kinase (RTK).

EphA1 was the first Eph receptor found in liver cancer cells when RTK was screened in 1987.

At present, there are 14 kinds of Eph receptors and 8 kinds of related ligands (adrenaline).

Eph receptors are classified into two types, A and B, according to their extracellular domains, which determine the binding affinity to ligands (Eph receptor interacting protein or adrenaline).

Nine EphA and 5 EphB receptors have been found in humans.

Eph receptor signals are involved in a variety of biological events, mainly causing rejection or adhesion between cells.

Therefore, Eph receptors and corresponding ligands have important functions in embryonic tissue configuration, neuron targeting, and blood vessel development.

At the same time, high levels of Eph protein are found in a variety of malignant tumors, and this overexpression greatly promotes the occurrence of cancer.

Some Eph receptors, especially EphA2, have attracted widespread attention because they have been shown to play an important role in the regulation of cancer occurrence and tumor progression (Figure 1).

This article gives an introduction to the EphA2 target and its relevance to cancer and treatment.

Figure 1.
The historical development and breakthrough of tumor targeting EphA2 EphA2 signaling pathway EphA2 receptor is a 130 kDa transmembrane glycoprotein containing 976 amino acids.

EphA2 can interact with any of 8 different Ephrin A family ligands, preferentially binding to Ephrin A1.

Ephrin A1 is a GPI-anchored protein that interacts with EphA2 to induce different signal networks after cell-to-cell contact.

Since both EphA2 receptor and Ephrin A1 ligand are membrane-bound, ligand-dependent activation triggers a unique two-way signal mechanism.
There is a "positive signal" in cells expressing EphA2 receptor, and Ephrin A1 ligand There is a "reverse signal" in the expressed cells (Figure 2).

The positive signal is usually rejected by the cell and promotes EphA2 oligomerization and phosphorylation, thereby enhancing kinase activity.

The direct biological consequences of EphA2 phosphorylation include decreased cell-extracellular matrix (ECM) attachment.

Ephrin A1: EphA2 induces and inhibits focal adhesion kinase (FAK), extracellular regulatory protein kinase (ERK) and Akt phosphorylation, thereby regulating the movement, vitality and proliferation of a variety of malignant tumor cell lines.

The reverse signal is more likely to be adhesive, because Ephrin A1 lacks enzyme activity.
Generally, the reverse signal is considered to be kinase-independent.
At present, the reverse signal sent by Ephrin A1 is still poorly understood.

Figure 2.
Bidirectional signaling mechanism of EphA2 receptor and Ephrin A1 ligand.
In addition, EphA2 has ligand-independent kinase activity in cancer cells.
For example, EphA2 has been shown to interact with E-cadherin, EGFR, HER2, and E-cadherin.
Integrin dimerizes and changes downstream signals in a non-canonical, ligand-independent manner, leading to its malignant effect in the non-phosphorylated state (Figure 3).

Figure 3.
EphA2 ligand-independent kinase activity.
Therefore, the interaction between EphA2 and Ephrin A1 or the EphA2 ligand-independent kinase activity may play a role through a combination of many factors, regulating embryonic development, angiogenesis, and tumorigenesis Multiple cellular processes (proliferation, survival, migration, morphology, intercellular rejection and adhesion).

Deciphering the many different mechanisms of EphA2 and Ephin A1 ligands in the physiological and pathological processes is still a challenge, but this provides an opportunity to determine which targeting strategies are most suitable for specific types of cancer where EphA2 plays a role in promoting cancer.

EphA2 and cancer are different from most Eph kinases synthesized during development.
EphA2 is mainly confined to adult hyperplastic epithelial cells. Adult EphA2 is only expressed in normal tissues when it has highly proliferating epithelial cells, and the importance and function of EphA2 are not very clear.

However, more and more evidence shows that human EphA2 is abundantly expressed in prostate cancer, lung cancer, esophageal cancer, colorectal cancer, cervical cancer, ovarian cancer, breast cancer and skin cancer.

The expression of EphA2 is associated with poor prognosis, increased metastatic potential and decreased survival time in cancer patients.

In addition, EphA2 is not only a biomarker of malignant features, but also an active participant in malignant progression.

Therefore, the transcription pattern of EphA2 and its functional relevance in malignant tumors make this protein an attractive target for cancer therapy.

Cancer treatment targeting EphA2 The EphA2/Ephrin A1 system can be used as a cancer treatment target through at least two mechanisms (Figure 4).

First, the carcinogenic function of EphA2 can be inhibited, such as reducing the expression of EphA2, promoting the degradation of EphA2, and blocking the activation of endogenous EphA2.

Alternatively, the EphA2 receptor can be used to deliver therapeutic drugs (exogenous drugs or endogenous immune cells) to cancer cells and related blood vessels.

Figure 4.
Targeting EphA2 mechanism of action in cancer EphA2 targeted therapy has appeared in clinical trials of various types and stages of malignant tumors.

Clinical strategies to inhibit EphA2 include EphA2 targeting antibody-cytotoxic drug conjugate (ADC) or peptide-drug conjugate (PDC); tyrosine kinase inhibitor (TKI), such as dasatinib, which has been approved for marketing; CAR-T cells that recognize and target EphA2 antigen; and nanocarriers designed to deliver siRNAs targeting EphA2 to tumor cells.

Potential future strategies to suppress non-canonical signals may also include EphA2 agonists, such as soluble EphA2 agonists (A1-Fc), or other small molecule inhibitors to block EphA2 phosphorylation at S897 (Akti/rski/PKAi) (Figure 5).

Figure 5.
EphA2 treatment targeting strategy Although there is a large amount of data to support the use of EphA2 drugs in cancer treatment, there are still some challenges.

The expression of EphA2 in multiple cell and tissue types represents both an opportunity and a challenge.

Expression in normal tissues may cause unexpected side effects.

The multiple signal modes of the EphA2 receptor also complicate the targeting strategy, and the most appropriate method may vary depending on the environment.

In addition, since EphA2 may be kinase-independent, traditional RTK small molecule inhibitors that block receptor kinase activity may not be able to inhibit EphA2 ligand-independent carcinogenic effects.

In spite of these challenges, the next generation of targeted therapies using reused drugs such as dasatinib and the peptide-toxin conjugates being developed are actively underway.

The editor concludes that in general, the important role of EphA2 in tumor biology makes it a promising therapeutic target.
The ongoing clinical efforts to target EphA2 may provide a valuable new weapon in the fight against cancer.
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Future efforts include continued in-depth understanding of EphA2-Ephrin A1 signaling and precise elucidation of crosstalk with other carcinogenic pathways.

Completed clinical studies and new biological discoveries provide clues for the development of next-generation EphA2 targeted therapies: (I) The focus should be on improving efficacy and selectivity, while preventing non-targeted side effects; (II) and other therapies Combined use may help.

Reference 1.
Oncogenic functions and therapeutic targeting of EphA2 in cancer.
Targeting EphA2 in cancer.
2.
Emerging and diverse functions of the EphA2 noncanonical pathway in cancer progression.
3.
Eph receptor signalling: from catalytic to non-catalytic functions.
4.
Emerging strategies for EphA2 receptor targeting for cancer therapeutics.
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