The structural basis of PI3K cancer mutations: from mechanism to therapy

Abstract

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.

Figure 1

Structural overview of the p85α/p110α complex: A: Schematic representations of the domain organization of both proteins. Boundaries were taken from Huang et al. The region of frequent mutation in p85 are indicated. B: Surface representation of the p85α/p110α complex. The p85a iSH2 domain is shown in ribbon representation. The region of deletions detected in cancer is highlighted in white. Cancer mutations are shown as sheres and are labeled. C: Rotated structure of the complex and details of the p85α nSH2 domain p110α interaction. A phosphopeptide binding to the SH2 domain is shown in ball and stick representation. D: Summary of TCGA data (8) showing the amino acid location of 884 exon mutations in p110α and p85α in 10 cancers. Vertical bars represent individual mutations. The number of mutations per tumour type and per domain is indicated. Ut: uterine endometrial cancer; Ov: ovarian cancer; Lusc: lung squamous cell carcinoma; Luad: lung adenocarcinoma; Kirc: kidney renal clear cell carcinoma; Hnsc: head & neck squamous cell carcinoma; Gbm: glioblastoma; Coad: colon and rectal adenocarcinomas; Brca: Breast cancer; Blca: Bladder cancer.