Frequent mutation of PI3K/AKT/mTOR signaling pathway genes in human cancers has stimulated large investments in targeted drugs but clinical successes are rare. As a result, many cancers with high PI3K pathway activity, such as triple-negative breast cancer (TNBC), are treated primarily with chemotherapy. By systematically analyzing responses of TNBC cells to a diverse collection of PI3K pathway inhibitors, we find that one drug, Torin2, is unusually effective because it inhibits both mTOR and other PI3K-like kinases (PIKKs). In contrast to mTOR-selective inhibitors, Torin2 exploits dependencies on several kinases for S-phase progression and cell-cycle checkpoints, thereby causing accumulation of single-stranded DNA and death by replication catastrophe or mitotic failure. Thus, Torin2 and its chemical analogs represent a mechanistically distinct class of PI3K pathway inhibitors that are uniquely cytotoxic to TNBC cells. This insight could be translated therapeutically by further developing Torin2 analogs or combinations of existing mTOR and PIKK inhibitors.

在人类癌症中，PI3K / AKT / mTOR信号通路基因的频繁突变刺激了对靶向药物的大量投资，但临床成功很少。结果，主要用化学疗法治疗具有高PI3K途径活性的许多癌症，例如三阴性乳腺癌（TNBC）。通过系统地分析TNBC细胞对多种PI3K途径抑制剂的反应，我们发现一种药物Torin2异常有效，因为它同时抑制mTOR和其他PI3K样激酶（PIKKs）。与mTOR选择性抑制剂相反，Torin2利用对S期进程和细胞周期检查点的几种激酶的依赖性，从而导致单链DNA的积累和复制灾难或有丝分裂失败导致死亡。因此，Torin2及其化学类似物代表了机械上独特的一类对TNBC细胞具有细胞毒性的PI3K途径抑制剂。通过进一步开发Torin2类似物或现有mTOR和PIKK抑制剂的组合，可以将这种见解进行治疗性翻译。