Mundi Prabhjot S, Sachdev Jasgit, McCourt Carolyn, Kalinsky Kevin
Division of Medical Oncology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
Br J Clin Pharmacol. 2016 Oct;82(4):943-56. doi: 10.1111/bcp.13021. Epub 2016 Jun 27.
The phosphatidylinositol-3 kinase (PI3K)-AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K-AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well-characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT.
磷脂酰肌醇-3激酶(PI3K)-AKT信号通路是所有癌症中最常失调的信号通路之一,在许多癌症中存在体细胞突变、拷贝数改变、异常表观遗传调控以及表达增加的情况。一方面,细胞分裂和生长的稳态平衡得到精心维持,另一方面,程序性细胞死亡也受到调控,而在肿瘤发生过程中,这种平衡普遍受到干扰,PI3K-AKT信号通路的下游效应器在这种干扰中发挥着重要作用。由于有大量下游效应器参与细胞存活和增殖,AKT已明确的直接相互作用使其成为极具吸引力但又难以捉摸的癌症治疗靶点。在此,我们综述该信号通路的显著特征、其在促进肿瘤发生中作用的证据以及靶向AKT治疗药物开发的最新进展。