文章：

三阴性乳腺癌中的PI3K/Akt/mTOR信号通路：耐药通路与靶向治疗的关键靶点

The PI3K/Akt/mTOR Signaling Pathway in Triple-Negative Breast Cancer: A Resistance Pathway and a Prime Target for Targeted Therapies

原文发布日期：3 July 2025

DOI: 10.3390/cancers17132232

类型: Article

开放获取: 是

英文摘要：

Triple-negative breast cancer is the most aggressive subtype of breast cancer and is associated with the worst prognosis. Conventional chemotherapy remains the gold standard treatment for this disease but is associated with a high relapse rate, highlighting the urgent need for effective targeted therapies. The PI3K/Akt/mTOR pathway, dysregulated in nearly 60% of these cancers, appears to be a prime target. It involves a signaling cascade beginning with PI3K activation followed by activating phosphorylation of Akt and then mTOR complex, which activates oncogenic processes by enhancing protein synthesis, inhibiting apoptosis, dysregulating autophagy and promoting DNA repair that supports tumor cell survival. Moreover, the PI3K/Akt/mTOR pathway plays a central role in the development of chemoresistance. Numerous alterations (activating the mutation of PIK3CA or the loss of tumor suppressor PTEN) may lead to its overactivation. Targeted inhibitors of PI3K, Akt and mTOR have been developed to counteract this dysregulation. However, numerous cancer resistance mechanisms have emerged, reducing their efficacy, for example, reactivation of Akt following mTOR blockade, reactivation of the pathway by insulin signaling or activation of compensatory pathways such as the MAPK pathway, thus limiting their integration into routine practice. To counteract these resistances, combination therapies currently being investigated in clinical trials aim to improve clinical outcomes of PI3K/Akt/mTOR pathway inhibition. The aim of this review was to summarize current therapies developed to target this pathway in TNBC, with a focus on the resistance mechanisms that limit their effectiveness.

摘要翻译： 

三阴性乳腺癌是乳腺癌最具侵袭性的亚型，预后最差。传统化疗仍是该疾病的标准治疗方案，但复发率高，凸显了对有效靶向治疗的迫切需求。PI3K/Akt/mTOR通路在近60%的三阴性乳腺癌中失调，是重要的治疗靶点。该通路通过级联信号传导发挥作用：PI3K激活后引发Akt磷酸化，进而激活mTOR复合物，通过增强蛋白质合成、抑制细胞凋亡、扰乱自噬调控及促进支持肿瘤细胞存活的DNA修复来驱动致癌进程。此外，该通路在化疗耐药形成中起核心作用，PIK3CA激活突变或抑癌基因PTEN缺失等多种变异均可导致其过度激活。为应对这一失调机制，已开发出针对PI3K、Akt和mTOR的靶向抑制剂。然而多种耐药机制的出现降低了其疗效，例如mTOR阻断后Akt的再激活、胰岛素信号通路引起的通路重启，以及MAPK通路等代偿通路的激活，这些因素限制了其临床常规应用。为克服耐药问题，目前临床试验正在探索联合治疗方案，旨在提升PI3K/Akt/mTOR通路抑制的临床疗效。本综述旨在系统总结针对该通路的现有三阴性乳腺癌治疗策略，并重点探讨限制其疗效的耐药机制。

原文链接：

The PI3K/Akt/mTOR Signaling Pathway in Triple-Negative Breast Cancer: A Resistance Pathway and a Prime Target for Targeted Therapies