Cancer is the second leading cause of human death globally. PI3K/Akt/mTOR signaling is one of the most frequently dysregulated signaling pathways observed in cancer patients that plays crucial roles in promoting tumor initiation, progression and therapy responses. This is largely due to that PI3K/Akt/mTOR signaling is indispensable for many cellular biological processes, including cell growth, metastasis, survival, metabolism, and others. As such, small molecule inhibitors targeting major kinase components of the PI3K/Akt/mTOR signaling pathway have drawn extensive attention and been developed and evaluated in preclinical models and clinical trials. Targeting a single kinase component within this signaling usually causes growth arrest rather than apoptosis associated with toxicity-induced adverse effects in patients. Combination therapies including PI3K/Akt/mTOR inhibitors show improved patient response and clinical outcome, albeit developed resistance has been reported. In this review, we focus on revealing the mechanisms leading to the hyperactivation of PI3K/Akt/mTOR signaling in cancer and summarizing efforts for developing PI3K/Akt/mTOR inhibitors as either mono-therapy or combination therapy in different cancer settings. We hope that this review will facilitate further understanding of the regulatory mechanisms governing dysregulation of PI3K/Akt/mTOR oncogenic signaling in cancer and provide insights into possible future directions for targeted therapeutic regimen for cancer treatment, by developing new agents, drug delivery systems, or combination regimen to target the PI3K/Akt/mTOR signaling pathway. This information will also provide effective patient stratification strategy to improve the patient response and clinical outcome for cancer patients with deregulated PI3K/Akt/mTOR signaling.

癌症是全球人类死亡的第二大原因。PI3K/Akt/mTOR 信号传导是在癌症患者中观察到的最常见失调的信号传导途径之一，在促进肿瘤发生、进展和治疗反应中起关键作用。这主要是因为 PI3K/Akt/mTOR 信号传导对于许多细胞生物学过程是必不可少的，包括细胞生长、转移、存活、新陈代谢等。因此，针对 PI3K/Akt/mTOR 信号通路主要激酶成分的小分子抑制剂已引起广泛关注，并在临床前模型和临床试验中得到开发和评估。靶向该信号中的单个激酶成分通常会导致生长停滞，而不是与毒性诱导的患者不良反应相关的细胞凋亡。包括 PI3K/Akt/mTOR 抑制剂在内的联合疗法显示出改善的患者反应和临床结果，尽管据报道产生了耐药性。在这篇综述中，我们重点揭示了导致癌症中 PI3K/Akt/mTOR 信号过度激活的机制，并总结了在不同癌症环境中开发 PI3K/Akt/mTOR 抑制剂作为单一疗法或联合疗法的努力。我们希望这篇综述将有助于进一步了解癌症中 PI3K/Akt/mTOR 致癌信号传导失调的调节机制，并通过开发新的药物、药物输送系统或联合方案靶向 PI3K/Akt/mTOR 信号通路。