PI3K/AKT/mTOR 通路在癌症中通常失调。 Rapalogs 表现出适度的临床益处，可能是由于它们对 4EBP1 缺乏影响。我们假设，在 mTORC1 功能障碍的肿瘤中，双位阻 mTORC1 选择性抑制剂比 rapalogs 具有更大的临床获益潜力。我们在体外和体内具有高 mTORC1 活性的肿瘤模型中评估了这一假设。双位阻抑制剂具有很强的生长抑制作用，消除了磷酸化的 4EBP1，并比雷帕霉素或 MLN0128 诱导更多的细胞凋亡。多组学分析显示，与雷帕霉素相比，双立体抑制剂具有广泛的作用。双立体异构体通过减少 JUN 及其下游靶标 PRPS1 选择性地抑制从头嘌呤合成，这似乎是细胞凋亡的原因。因此，双位阻 mTORC1 选择性抑制剂是治疗由 mTORC1 过度激活驱动的肿瘤的治疗策略。

The PI3K/AKT/mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit, likely owing to their lack of effects on 4EBP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multiomics analysis showed extensive effects of the bi-steric inhibitors in comparison with rapamycin. De novo purine synthesis was selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.