Radiotherapy remains the mainstay for treatment of various types of human cancer; however, the clinical efficacy is often limited by radioresistance, in which the underlying mechanism is largely unknown. Here, using esophageal squamous cell carcinoma (ESCC) as a model, we demonstrate that guanine nucleotide exchange factor 2 (VAV2), which is overexpressed in most human cancers, plays an important role in primary and secondary radioresistance. We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation. We show that VAV2 overexpression substantially upregulates signal transducer and activator of transcription 1 (STAT1) and the STAT1 inhibitor Fludarabine can significantly promote the sensitivity of radioresistant patient-derived ESCC xenografts in vivo in mice to radiotherapy. These results shed new light on the mechanism of cancer radioresistance, which may be important for improving clinical radiotherapy.

放射疗法仍然是治疗各种人类癌症的主要手段；然而，临床疗效通常受到放射抗性的限制，其中潜在的机制在很大程度上是未知的。在这里，我们使用食管鳞状细胞癌 (ESCC) 作为模型，证明在大多数人类癌症中过度表达的鸟嘌呤核苷酸交换因子 2 (VAV2) 在原发性和继发性放射抗性中起重要作用。我们首次发现VAV2是Ku70/Ku80复合物形成所必需的，并参与了电离辐射引起的DNA损伤的非同源末端连接修复。我们表明，VAV2 过表达显着上调了信号转导和转录激活因子 1 (STAT1)，而 STAT1 抑制剂氟达拉滨可以显着提高小鼠体内抗辐射患者衍生的 ESCC 异种移植物对放射治疗的敏感性。这些结果为癌症放射抗性机制提供了新的启示，这可能对改善临床放射治疗具有重要意义。