Klempner Samuel J, Myers Andrea P, Cantley Lewis C
1Division of Hematology-Oncology, University of California Irvine Medical Center, Orange, California; 2Division of Signal Transduction, Beth Israel Deaconess Medical Center; 3Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; and 4Department of Medicine, Weill Cornell Medical College, New York, New York.
Cancer Discov. 2013 Dec;3(12):1345-54. doi: 10.1158/2159-8290.CD-13-0063. Epub 2013 Nov 21.
The phosphoinositide 3-kinase (PI3K) pathway is one of the most frequently mutated pathways in cancer, and is actively being pursued as a therapeutic target. Despite the importance of the PI3K pathway in cancer, durable responses to PI3K pathway-targeted therapies are uncommon with monotherapy. Several in vitro and xenograft models have elucidated compensatory signaling and genomic changes which may limit the therapeutic effectiveness of PI3K inhibitors in the clinic. Future clinical trials with prospective evaluation of tumor signaling and genomic changes are likely to identify novel resistance mechanisms as well as subsets of patients who may derive maximal benefit from PI3K pathway inhibitors.
There are multiple ongoing clinical trials targeting the PI3K pathway members in several malignancies. This review summarizes the known mechanisms of resistance to targeting the PI3K pathway. Understanding of resistance mechanisms will help to inform more rational clinical trial design to optimize the clinical impact of targeting the PI3K pathway in cancer.
磷酸肌醇3激酶（PI3K）信号通路是癌症中最常发生突变的信号通路之一，目前正积极探索将其作为治疗靶点。尽管PI3K信号通路在癌症中具有重要作用，但单药治疗对PI3K信号通路靶向治疗的持久反应并不常见。多个体外和异种移植模型已经阐明了补偿性信号传导和基因组变化，这可能会限制PI3K抑制剂在临床上的治疗效果。未来对肿瘤信号传导和基因组变化进行前瞻性评估的临床试验可能会识别出新的耐药机制以及可能从PI3K信号通路抑制剂中获得最大益处的患者亚组。
目前有多项针对几种恶性肿瘤中PI3K信号通路成员的正在进行的临床试验。本综述总结了已知的针对PI3K信号通路的耐药机制。了解耐药机制将有助于更合理地设计临床试验，以优化针对癌症中PI3K信号通路的临床疗效。
