Sarah Cannon Research Institute, 3322 West End Avenue, Suite 900, Nashville, TN 37203, USA.
Cancer Chemother Pharmacol. 2013 Apr;71(4):829-42. doi: 10.1007/s00280-012-2043-3. Epub 2013 Feb 3.
Most targeted anticancer therapies, as well as cytotoxic and radiation therapies, are encumbered by the development of secondary resistance by cancer cells. Resistance is a complex phenomenon involving multiple mechanisms, including activation of signaling pathways such as phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR). Novel strategies to overcome resistance by targeting these signaling pathways are being evaluated.
PubMed and key cancer congress abstracts were searched until July 2012 for preclinical and clinical data relating to the PI3K/AKT/mTOR pathway and anticancer treatment resistance, and use of PI3K/AKT/mTOR inhibitors in resistant cancer cell lines and patient populations.
Activation of the PI3K/AKT/mTOR pathway is frequently implicated in resistance to anticancer therapies, including biologics, tyrosine kinase inhibitors, radiation, and cytotoxics. As such, inhibitors of the PI3K/AKT/mTOR pathway are being rapidly evaluated in preclinical models and in clinical studies to determine whether they can restore therapeutic sensitivity when given in combination. In breast cancer, non-small-cell lung cancer, and glioblastoma, we find compelling preclinical evidence to show that inhibitors of PI3K or mTOR can restore sensitivity in resistant cells. Although clinical evidence is less mature, a recent Phase III study with the mTORC1 inhibitor everolimus in patients with advanced breast cancer resistant to aromatase inhibition and several Phase I/II studies with PI3K inhibitors demonstrate proof-of-concept, warranting future clinical evaluation.
Current preclinical and clinical evidence suggest that inhibitors of the PI3K/AKT/mTOR pathway could have utility in combination with other anticancer therapies to circumvent resistance by cancer cells. Multiple clinical studies are ongoing.
大多数靶向抗癌疗法以及细胞毒性和放射疗法都受到癌细胞产生继发性耐药的阻碍。耐药是一种涉及多种机制的复杂现象，包括激活信号通路，如磷脂酰肌醇 3-激酶（PI3K）/AKT/哺乳动物雷帕霉素靶蛋白（mTOR）。目前正在评估针对这些信号通路的新策略以克服耐药性。
直到 2012 年 7 月，我们在 PubMed 和主要癌症大会摘要中搜索了与 PI3K/AKT/mTOR 通路和抗癌治疗耐药性相关的临床前和临床数据，以及在耐药癌细胞系和患者群体中使用 PI3K/AKT/mTOR 抑制剂的情况。
PI3K/AKT/mTOR 通路的激活常常与抗癌疗法的耐药性有关，包括生物制剂、酪氨酸激酶抑制剂、放疗和细胞毒性药物。因此，PI3K/AKT/mTOR 通路抑制剂正在快速在临床前模型和临床研究中进行评估，以确定它们在联合应用时是否可以恢复治疗敏感性。在乳腺癌、非小细胞肺癌和胶质母细胞瘤中，我们发现有令人信服的临床前证据表明，PI3K 或 mTOR 的抑制剂可以恢复耐药细胞的敏感性。尽管临床证据还不够成熟，但最近一项针对晚期乳腺癌患者的 III 期研究显示，mTORC1 抑制剂依维莫司对芳香酶抑制剂耐药有效，并且多项针对 PI3K 抑制剂的 I/II 期研究也提供了概念验证，值得进一步的临床评估。
目前的临床前和临床证据表明，PI3K/AKT/mTOR 通路抑制剂与其他抗癌疗法联合使用可能有助于克服癌细胞的耐药性。目前正在进行多项临床研究。
