The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target

Abstract

Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.

KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors

“…Our laboratory has recently shown that KSR1 also promotes anchorageindependent growth and tumor maintenance in human colon tumor cell lines (16 (16,19,44,45), the similarity of siKSR1-and siEPHB4-dependent gene expression signatures suggests that EPHB4 is likely to support colon tumor cell survival similarly to KSR1. EPHB4 expression is elevated in a variety of human cancers, including cancers of the head and neck, prostate, bladder, ovaries, large intestine, lung, brain, pancreas, and esophagus (46)(47)(48)(49)(50)(51)(52)(53)(54). We analyzed the expression of EPHB4 in a panel of colon tumor cells compared to its expression in HCECs.…”

“…The mechanistic role that EPHB4 plays in cancer remains controversial. However, a preponderance of data indicate that EPHB4 is overexpressed broadly in human cancers, including cancers of the head and neck, prostate, bladder, ovaries, large intestine, lung, brain, pancreas, and esophagus (46)(47)(48)(49)(50)(51)(52)(53)(54). Further research has shown that the ablation or inhibition of EPHB4 in a number of cancer cell types reduces tumor cell viability, including prostate (47), bladder (48), ovarian (49), colon (50), lung (51), head and neck squamous cell carcinoma (74), and esophageal (54) cancer.…”

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…(77,81) The Eph receptors/ephrins have also been implicated in tumourigenesis, progression and metastasis across a wide range of malignancies (Table 3). ( (83) Prostate cancer (84,85) Breast cancer (86,87) Melanoma (88) Glioblastoma (89,90) Gastric cancer (91) EphA3 Gastric cancer (92) Colorectal cancer (93) EphB2 Advanced cSCC (94) Glioblastoma (95)(96)(97) Cervical cancer (98) Breast cancer (99) EphB4 HNSCC (100) Non-small cell lung cancer (101) Breast cancer (99) Downregulated EphA1 NMSC (77) …”

The Role of EphB4 and Ephrin-B2 Interactions in Prostate Cancer Models of Intravasation and Extravasation

“…The sole, physiologically relevant ligand for EphB4 is ephrin-B2, a transmembrane protein expressed on the surface of certain cells, which interacts with EphB4 on adjacent cells during cell-to-cell contact. Data supports a role for EphB4-ephrin-B2 interaction in tumour angiogenesis and suggests that EphB4 positive tumour cells may preferentially attach to ephrin-B2 expressing endothelial cells during extravasation which is the process of translocation of circulating tumour cells out of blood vessels into surrounding tissues, thereby promoting metastatic spread [14][15][16][17][18][19].…”

“…EphB4 is a protein receptor expressed in increased amounts on the surface of cancer cells, including those from the prostate, and its function has been linked to several processes important for metastatic spread, including cell viability, migration, invasion and adhesion [14][15][16][17][18][19]. The sole, physiologically relevant ligand for EphB4 is ephrin-B2, a transmembrane protein expressed on the surface of certain cells, which interacts with EphB4 on adjacent cells during cell-to-cell contact.…”