Targeting EPHA2 with Kinase Inhibitors in Colorectal Cancer

Tröster, Alix; Jores, Nathalie; Mineev, Konstantin S.; Sreeramulu, Sridhar; DiPrima, Michael; Tosato, Giovanna; Schwalbe, Harald

doi:10.1002/cmdc.202300420

Cited by 8 publications

(3 citation statements)

References 72 publications

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“…This results in enhancing the antiapoptotic AKT signaling pathway and promoting cancer stemness [274]. Directly targeting EphA2 with a tyrosine kinase inhibitor decreases cell proliferation and induces cell death in CRC cells [275][276][277]. Based on the finding that, in response to DNA damage, the ephrinB2-encoding gene is a transcriptional target of p53, a key apoptosis regulatory protein, knock down of ephrinB2 expression was used to restore apoptosis and 5-FU chemosensitivity in mutant p53-harboring CRC tumors [278].…”

Section: Surviving Attacksmentioning

confidence: 99%

Cell Death, by Any Other Name…

Kandouz

2024

Cells

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Studies trying to understand cell death, this ultimate biological process, can be traced back to a century ago. Yet, unlike many other fashionable research interests, research on cell death is more alive than ever. New modes of cell death are discovered in specific contexts, as are new molecular pathways. But what is “cell death”, really? This question has not found a definitive answer yet. Nevertheless, part of the answer is irreversibility, whereby cells can no longer recover from stress or injury. Here, we identify the most distinctive features of different modes of cell death, focusing on the executive final stages. In addition to the final stages, these modes can differ in their triggering stimulus, thus referring to the initial stages. Within this framework, we use a few illustrative examples to examine how intercellular communication factors in the demise of cells. First, we discuss the interplay between cell–cell communication and cell death during a few steps in the early development of multicellular organisms. Next, we will discuss this interplay in a fully developed and functional tissue, the gut, which is among the most rapidly renewing tissues in the body and, therefore, makes extensive use of cell death. Furthermore, we will discuss how the balance between cell death and communication is modified during a pathological condition, i.e., colon tumorigenesis, and how it could shed light on resistance to cancer therapy. Finally, we briefly review data on the role of cell–cell communication modes in the propagation of cell death signals and how this has been considered as a potential therapeutic approach. Far from vainly trying to provide a comprehensive review, we launch an invitation to ponder over the significance of cell death diversity and how it provides multiple opportunities for the contribution of various modes of intercellular communication.

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Section: Surviving Attacksmentioning

confidence: 99%

Cell Death, by Any Other Name…

Kandouz

2024

Cells

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“…Additionally, both receptors are implicated in cancer. Although EphA2 expression is usually low in normal adult tissue, EphA2 overexpression in certain tumors is often correlated with poor prognosis (15)(16)(17). The Smith Lab and collaborators recently showed how different multimerization interfaces contributed to distinct downstream signaling and oncogenic functions (18).…”

Section: Introductionmentioning

confidence: 99%

Phosphatidylinositol (4,5)-bisphosphate drives the formation of EGFR and EphA2 complexes

Singh,

Rybak,

Schuck

et al. 2024

Preprint

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Receptor tyrosine kinases (RTKs) regulate many cellular functions and are important targets in pharmaceutical development, particularly in cancer treatment. EGFR and EphA2 are two key RTKs that are associated with oncogenic phenotypes. Several studies have reported functional interplay between these receptors, but the mechanism of interaction is still unresolved. Here we utilize a time-resolved fluorescence spectroscopy called PIE-FCCS to resolve EGFR and EphA2 interactions in live cells. We tested the role of ligands and found that EGF, but not ephrin A1 (EA1), stimulated hetero-multimerization between the receptors. To determine the effect of anionic lipids, we targeted phospholipase C (PLC) activity to alter the abundance of phosphatidylinositol (4,5)-bisphosphate (PIP2). We found that higher PIP2 levels increased homo-multimerization of both EGFR and EphA2, as well as hetero-multimerization. This study provides a direct characterization of EGFR and EphA2 interactions in live cells and shows that PIP2 can have a substantial effect on the spatial organization of RTKs.

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“…Many pharmacological tools targeting the Eph-ephrin system have been discovered and proven their activity in many preclinical models. Recently, Tröster and colleagues summarized the rational use of EphA2 kinase inhibitors, such as NVP-BHG712, GLPG1790, and ALW-II-41-27, in cetuximab-resistant colon rectal cancer [14]. Instead, anti-EphA5 mAb 11C12 and Eph and ephrin recombinant proteins, together with tyrosine kinase inhibitors targeting Eph receptors such as Dasatinib and Osimertinib, have shown promising results in preclinical models of lung cancer [15].…”

Section: Introductionmentioning

confidence: 99%

A Pharmacological Investigation of Eph-Ephrin Antagonism in Prostate Cancer: UniPR1331 Efficacy Evidence

Festuccia,

Corrado,

Rossetti

et al. 2023

Pharmaceuticals

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The Eph kinases are the largest receptor tyrosine kinases (RTKs) family in humans. PC3 human prostate adenocarcinoma cells are a well-established model for studying Eph–ephrin pharmacology as they naturally express a high level of EphA2, a promising target for new cancer therapies. A pharmacological approach with agonists did not show significant efficacy on tumor growth in prostate orthotopic murine models, but reduced distal metastasis formation. In order to improve the comprehension of the pharmacological targeting of Eph receptors in prostate cancer, in the present work, we investigated the efficacy of Eph antagonism both in vitro and in vivo, using UniPR1331, a small orally bioavailable Eph–ephrin interaction inhibitor. UniPR1331 was able to inhibit PC3 cells’ growth in vitro in a dose-dependent manner, affecting the cell cycle and inducing apoptosis. Moreover, UniPR1331 promoted the PC3 epithelial phenotype, downregulating epithelial mesenchymal transition (EMT) markers. As a consequence, UniPR1331 reduced in vitro PC3 migration, invasion, and vasculomimicry capabilities. The antitumor activity of UniPR1331 was confirmed in vivo when administered alone or in combination with cytotoxic drugs in PC3-xenograft mice. Our results demonstrated that Eph antagonism is a promising strategy for inhibiting prostate cancer growth, especially in combination with cytotoxic drugs.

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Targeting EPHA2 with Kinase Inhibitors in Colorectal Cancer

Cited by 8 publications

References 72 publications

Cell Death, by Any Other Name…

Cell Death, by Any Other Name…

Phosphatidylinositol (4,5)-bisphosphate drives the formation of EGFR and EphA2 complexes

A Pharmacological Investigation of Eph-Ephrin Antagonism in Prostate Cancer: UniPR1331 Efficacy Evidence

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