Tumor acquired radioresistance remains as the major limit in cancer radiotherapy (RT). Rab25, a receptor recycling protein, has been reported to be enhanced in tumors with aggressive phenotype and chemotherapy resistance. In this study, elevated Rab25 expression was identified in an array of radioresistant human cancer cell lines, in vivo radioresistant xenograft tumors. Clinical investigation confirmed that Rab25 expression was also associated with a worse prognosis in patients with lung adenocarcinoma (LUAD) and nasopharyngeal carcinoma (NPC). Enhanced activities of EGFR were observed in both NPC and LUAD radioresistant cells. Rab25 interacts with EGFR to enhance EGFR recycling to cell surface and to decrease degradation in cytoplasm. Inhibition of Rab25 showed synergized radiosensitivity with reduced aggressive phenotype. This study provides the clinical and experimental evidence that Rab25 is a potential therapeutic target to alleviate the hyperactive EGFR signaling and to prevent RT-acquired tumor resistance in patients with LUAD and NPC.

肿瘤获得性放射抗性仍然是癌症放射治疗 (RT) 的主要限制。据报道，Rab25 是一种受体循环蛋白，在具有侵袭性表型和化疗耐药性的肿瘤中增强。在这项研究中，在体内的一系列抗辐射人类癌细胞系中发现了升高的 Rab25 表达抗辐射异种移植肿瘤。临床研究证实，Rab25 表达也与肺腺癌 (LUAD) 和鼻咽癌 (NPC) 患者的预后较差有关。在 NPC 和 LUAD 抗辐射细胞中都观察到 EGFR 的活性增强。Rab25 与 EGFR 相互作用以增强 EGFR 再循环到细胞表面并减少细胞质中的降解。Rab25 的抑制显示出协同放射敏感性和降低的侵袭性表型。本研究提供了临床和实验证据，表明 Rab25 是缓解过度活跃的 EGFR 信号传导和预防 LUAD 和 NPC 患者 RT 获得性肿瘤耐药的潜在治疗靶点。