Merck Research Laboratories, Boston, MA.
Transl Oncol. 2012 Dec;5(6):422-9. doi: 10.1593/tlo.12241. Epub 2012 Dec 1.
Activation of the phosphoinositide 3-kinase pathway is commonly observed in human prostate cancer. Loss of function of phosphatase and tensin homolog (PTEN) is associated with the activation of AKT and mammalian target of rapamycin (mTOR) in many cancer cell lines as well as in other model systems. However, activation of mTOR is also dependent of kinases other than AKT. Here, we show that activation of mTOR is not dependent on AKT in a prostate-specific PTEN-deficient mouse model of prostate cancer. Pathway bifurcation of AKT and mTOR was noted in both mouse and human prostate tumors. We demonstrated for the first time that cotargeting mTOR and AKT with ridaforolimus/MK-8669 and M1K-2206, respectively, delivers additive antitumor effects in vivo when compared to single agents. Our preclinical data suggest that the combination of AKT and mTOR inhibitors might be more effective in treating prostate cancer patients than current treatment regimens or either treatment alone.
磷酸肌醇 3-激酶途径的激活在人类前列腺癌中很常见。在许多癌细胞系以及其他模型系统中，磷酸酶和张力蛋白同系物 (PTEN) 的功能丧失与 AKT 和哺乳动物雷帕霉素靶蛋白 (mTOR) 的激活有关。然而，mTOR 的激活也依赖于 AKT 以外的激酶。在这里，我们在前列腺特异性缺失 PTEN 的前列腺癌小鼠模型中表明，mTOR 的激活不依赖于 AKT。在小鼠和人类前列腺肿瘤中都观察到 AKT 和 mTOR 的途径分岔。我们首次证明，与单药治疗相比，用 ridaforolimus/MK-8669 和 M1K-2206 分别靶向 mTOR 和 AKT 的联合治疗在体内具有相加的抗肿瘤作用。我们的临床前数据表明，与目前的治疗方案或单独使用任何一种治疗相比，AKT 和 mTOR 抑制剂的联合使用可能更有效地治疗前列腺癌患者。
