Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors
Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors
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DOI：
10.1200/jco.2014.59.0018
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发表时间：
2016-11-01
影响因子：
45.3
通讯作者：
LoRusso, Patricia Mucci
中科院分区：
文献类型：
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作者：
LoRusso, Patricia Mucci
磷酸肌醇3-激酶（PI 3 K）通路在许多细胞过程中起着不可或缺的作用，并且在癌症中经常发生改变，有助于肿瘤生长和存活。已经开发了靶向该途径的三个主要节点的小分子抑制剂：PI 3 K、AKT和雷帕霉素的哺乳动物靶标。然而，由于致癌PI 3 K通路激活是以多种可能冗余的方式实现的，因此这些抑制剂作为单药治疗的临床疗效迄今为止有限，尽管显示出有希望的临床前活性。此外，通路激活与对其他疗法的耐药性相关;因此，联合使用PI 3 K通路抑制剂可以恢复对这些药物的治疗敏感性。必须探索最大化治疗益处、药物组合和方案，以确定具有最高疗效和最低毒性重叠的药物。此外，对于单药治疗和联合用药，确定适当的患者亚群也很重要。然而，识别预测性生物标志物仍然是一个挑战。(C)2016年美国临床肿瘤学会
The phosphoinositide 3-kinase (PI3K) pathway plays an integral role in many cellular processes and is frequently altered in cancer, contributing to tumor growth and survival. Small molecule inhibitors have been developed that target the three major nodes of this pathway: PI3K, AKT, and mammalian target of rapamycin. However, because oncogenic PI3K pathway activation is achieved in diverse, potentially redundant ways, the clinical efficacy of these inhibitors as monotherapies has, so far, been limited, despite demonstrating promising preclinical activity. Moreover, pathway activation is associatedwith resistance to other therapies; thus, in combination, PI3K pathway inhibitors could restore therapeutic sensitivity to these agents. Tomaximize therapeutic benefit, drug combinations and schedules must be explored to identify those with the highest efficacy and lowest toxicity overlap. In addition, defining appropriate patient subpopulations, for both monotherapy and drug combinations, will be important. However, identifying predictive biomarkers remains a challenge. (C) 2016 by American Society of Clinical Oncology