PI3K 与癌症：教训、挑战与机遇。
PI3K and cancer: lessons, challenges and opportunities.
机构信息
Department of Molecular Biology & Biochemistry, and Institute for Immunology, University of California, Irvine, 3242 McGaugh Hall, Irvine, California 92697, USA.
Amgen Inc., Thousand Oaks, One Amgen Center Drive, California 91320, USA.
出版信息
Nat Rev Drug Discov. 2014 Feb;13(2):140-56. doi: 10.1038/nrd4204.
The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kδ inhibitors in chronic lymphocytic leukaemia, where a combination of cell-intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents.
磷酸肌醇 3-激酶 (PI3K) 的激活在肿瘤细胞生物学中起着核心作用，这促使人们大力研究针对 PI3K 及其下游激酶（如 AKT 和雷帕霉素靶蛋白 (mTOR)）的靶点，以治疗癌症。然而，新兴的临床数据表明，在可耐受剂量下，针对 PI3K、AKT 或 mTOR 的抑制剂的单一药物活性有限。一个例外是 PI3Kδ 抑制剂在慢性淋巴细胞白血病中的反应，其中细胞内和细胞外活动的组合驱动疗效。在这里，我们回顾了针对 PI3K-AKT-mTOR 通路抑制剂的临床开发的关键挑战和机遇。通过更加关注患者选择、加深对免疫调节的理解以及合理组合的策略应用，应该有可能实现这一有前途的靶向抗癌药物类别的潜力。
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