Mechanistic target of rapamycin (mTOR) forms two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2. Here we investigated the antitumor effect of dual mTORC1/2 inhibitor AZD2014 on epithelial ovarian cancer (EOC) and its potential effect on immunosuppressive myeloid-derived suppressor cells (MDSCs). Immunohistochemical analysis of mTORC1 and mTORC2 was performed on a human ovarian cancer tissue microarray. High mTORC2 expression level was associated with shorter survival in EOC, whereas mTORC1 was not correlate with patients’ prognosis. AZD2014 suppressed mTOR signaling pathway in ovarian cancer cells, inhibited proliferation and induced G1-phase cell cycle arrest and apoptosis. In tumor-bearing mice, AZD2014 treatment limited tumor growth, reduced peritoneal ascites, and prolonged survival. AZD2014 specifically reduced MDSCs migration and accumulation in EOC peritoneal fluid but not in the spleen. Moreover, subsequent AZD2014 treatment after cisplatin chemotherapy delayed EOC recurrence. Collectively, we observed that high mTORC2 expression level in EOC indicated a poor prognosis. Remarkably, in tumor-bearing mice, AZD2014 diminished MDSC accumulation and delayed tumor growth and recurrence.

雷帕霉素的机械靶点 (mTOR) 形成两个不同的复合物，mTOR 复合物 1 (mTORC1) 和 mTORC2。在这里，我们研究了双重 mTORC1/2 抑制剂 AZD2014 对上皮性卵巢癌 (EOC) 的抗肿瘤作用及其对免疫抑制性骨髓源性抑制细胞 (MDSCs) 的潜在影响。mTORC1 和 mTORC2 的免疫组织化学分析在人类卵巢癌组织微阵列上进行。高 mTORC2 表达水平与 EOC 中较短的生存期相关，而 mTORC1 与患者的预后无关。AZD2014 抑制卵巢癌细胞中的 mTOR 信号通路，抑制增殖并诱导 G1 期细胞周期停滞和凋亡。在荷瘤小鼠中，AZD2014 治疗限制了肿瘤的生长，减少了腹水，延长了生存期。AZD2014 特异性地减少了 EOC 腹膜液中的 MDSCs 迁移和积累，但在脾脏中没有。此外，顺铂化疗后随后的 AZD2014 治疗延缓了 EOC 复发。总的来说，我们观察到 EOC 中 mTORC2 的高表达水平表明预后不良。值得注意的是，在荷瘤小鼠中，AZD2014 减少了 MDSC 的积累并延缓了肿瘤的生长和复发。