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.
Highlights
Numerous drug targets have been studied extensively, the overall survival of lung cancer has improved only minimally over the past four decades [1]
Zheng et al found that EphB4 is expressed more strongly in tumor tissues compared to paired normal samples and that expression was positively correlated with clinical stage [38]
It is interesting that squamous cell carcinoma (SCC) featured the most prevalent degree of increase in gene copy number while having a relatively homogeneous expression profile
Summary
Numerous drug targets have been studied extensively, the overall survival of lung cancer has improved only minimally over the past four decades [1]. One frequent characteristic of lung cancer is an aberration in which one or more receptor tyrosine kinases (RTKs), such as MET, EGFR, and ALK, are commonly overexpressed, amplified, or mutated [2,3,4]. The Eph family is the largest family of RTKs, comprising fourteen mammalian receptors that interact with eight mammalian ligands, or ephrins. Eph receptors and ephrin ligands are organized functionally and structurally into A- and B-classes [5]. Eph receptors are relatively similar across classes; the membrane-bound ephrin-B ligands are unique in that they possess extracellular domains that activate receptors as well as intracellular domains that are thought to signal downstream within an adjacent cell [6]. There is some promiscuity among receptor and ligand interactions; one of the most specific receptor-ligand interactions, is between EphB4 and ephrin-B2 [7]
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