Eph/ephrin family proteins and therapeutic resistance

Karam, Sana D.

doi:10.1016/b978-0-12-817868-3.00009-3

Cited by 1 publication

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“…The receptor tyrosine kinase EphB4 and its preferred membrane-bound ligand ephrinB2 play a crucial role in both physiological angiogenesis and lymphangiogenesis during embryonic development as well as in pathophysiological processes such as tumor angiogenesis [1][2][3][4][5]. Moreover, EphB4 and ephrinB2 gained increasing attention with regard to therapy resistance in different solid tumors such as head and neck squamous cell carcinoma (HNSCC), pancreatic adenocarcinoma (PDAC), and bladder urothelial carcinoma [6][7][8][9]. For example, EphB4 has been identified as a predictive biomarker for the therapy response of colorectal cancer patients receiving the vascular endothelial growth factor (VEGF)-targeting antibody bevacizumab, with an increased EphB4 expression in non-responders [6].…”

Section: Introductionmentioning

confidence: 99%

The Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitor NVP-BHG712: Effects of Regioisomers on Tumor Growth, Perfusion, and Hypoxia in EphB4-Positive A375 Melanoma Xenografts

et al. 2020

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In a previous study, EphB4 was demonstrated to be a positive regulator of A375melanoma growth but a negative regulator of tumor vascularization and perfusion. To distinguish between EphB4 forward and ephrinB2 reverse signaling, we used the commercially available EphB4 kinase inhibitor NVPBHG712 (NVP), which was later identified as its regioisomer NVPiso. Since there have been reported significant differences between the inhibition profiles of NVP and NVPiso, we compared the influence of NVP and NVPiso on tumor characteristics under the same experimental conditions. Despite the different inhibitory profiles of NVP and NVPiso, the comparative study conducted here showed the same EphB4-induced effects in vivo as in the previous investigation. This confirmed the conclusion that EphB4-ephrinB2 reverse signaling is responsible for increased tumor growth as well as decreased tumor vascularization and perfusion. These results are further substantiated by microarrays showing differences between mock-transfected and EphB4-transfected (A375-EphB4) cells with respect to at least 9 angiogenesis-related proteins. Decreased expression of vascular endothelial growth factor (VEGF), angiotensin 1 (Ang-1), and protein kinase B (Akt/PKB), together with the increased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and transforming growth factor beta-2 (TGF-β2), is consistent with the impaired vascularization of A375-EphB4 xenografts. Functional overexpression of EphB4 in A375-EphB4 cells was confirmed by activation of a variety of signaling pathways, including the Janus kinase/signal transducers and activators of transcription (JAK/STAT), rat sarcoma virus/rapidly accelerated fibrosarcoma/mitogen activated protein kinase kinase (Ras/Raf/MEK), and nuclear factor kappa-B (NFkB) pathways.

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