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

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.尽管肺癌的局部区域治疗与全身治疗已取得诸多进展，但患者的生存预后仍不容乐观。受体酪氨酸激酶（Receptor Tyrosine Kinases）常参与肺癌的发病进程，部分酪氨酸激酶抑制策略已在临床中展现出确切疗效。近期，EphB4受体酪氨酸激酶（EphB4 Receptor Tyrosine Kinase）在多种其他恶性肿瘤中被鉴定为潜在治疗靶点。本研究旨在系统探究EphB4在肺癌中的生物学功能与临床意义。本研究证实，相较于配对正常组织，肺癌组织中EphB4的表达量上调3倍，且肺癌样本中常出现该基因的拷贝数扩增。本研究同时发现，EphB4过表达可促进细胞增殖、集落形成与细胞迁移能力；而抑制EphB4则可在体外降低细胞活力，作为单靶点治疗策略时可阻断小鼠异种移植模型中已形成肿瘤的生长，与紫杉醇（paclitaxel）联合使用时则可使已形成的肿瘤近乎完全消退。综上，上述研究结果表明EphB4可作为肺癌潜在的新型治疗靶点，发挥关键作用。因此，开展评估抗EphB4治疗方案以及含EphB4抑制的联合治疗方案疗效的临床试验具备充分合理性。