The structural basis of PI3K cancer mutations: from mechanism to therapy.
While genetic alteration in the p85α-p110α (PI3K) complex represents one of the most frequent driver mutations in cancer, the wild-type complex is also required for driving cancer progression through mutations in related pathways. Understanding the mechanistic basis of the function of the phosphoinositide 3-kinase (PI3K) is essential for designing optimal therapeutic targeting strategies. Recent structural data of the p85α/p110α complex unraveled key insights into the molecular mechanisms of the activation of the complex and provided plausible explanations for the well-established biochemical data on p85/p110 dimer regulation. A wealth of biochemical and biologic information supported by recent genetic findings provides a strong basis for additional p110-independent function of p85α in the regulation of cell survival. In this article, we review the structural, biochemical, and biologic mechanisms through which p85α regulates the cancer cell life cycle with an emphasis on the recently discovered genetic alterations in cancer. As cancer progression is dependent on multiple biologic processes, targeting key drivers such as the PI3K may be required for efficacious therapy of heterogeneous tumors typically present in patients with late-stage disease.
Authors' Affiliations: Weatherall Institute of Molecular Medicine, University of Oxford, Headington; Nuffield Department of Obstetrics and Gynaeoclogy, Women's Centre, John Radcliffe Hospital; Nuffield Department of Clinical Medicine, SGC, Oxford, United Kingdom; and Xijing Hospital, the Fourth Military Medical University, Shaanxi Province, China.
Shujuan
S
Liu
Stefan
S
Knapp
Ahmed Ashour
AA
Ahmed
D004789:Enzyme Activation; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
D019869:Phosphatidylinositol 3-Kinases