Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K–AKT–mTOR pathway inhibitors in breast cancer.

PI3K-AKT-mTOR信号网络的失调是乳腺癌的一个突出特征。但是，针对靶向该途径的药物的临床反应一直很温和，这可能是由于细胞信号传导中的动态变化驱动了耐药性并限制了药物功效。使用定量化学蛋白质组学方法，我们绘制了响应该途径抑制剂的动力学图谱，并确定了与药物敏感性相关的信号变化。药物治疗后维持AURKA与乳腺癌模型的耐药性有关。对AURKA的不完全抑制是治疗失败的常见原因，PI3K，AKT或mTOR抑制剂与AURKA抑制剂MLN8237的组合具有高度协同作用，并持久抑制了mTOR信号传导，导致体内凋亡和肿瘤消退。