PI 3-kinase and cancer: changing accents

Abstract

Research on PI 3-kinase (PI3K) is undergoing significant shifts in emphasis. Questions that have been dormant for some time are coming to the forefront, such as the relationship of PTEN to PI3K and the role of AKT in PI3K-driven oncogenesis. Two non-alpha isoforms of Class I PI3K are now established as important determinants in cancer: p110beta and p110delta. The oncogenic activities of p110beta include a non-catalytic function, a finding that will have immediate consequences for drug development.

Figure 1

The pathway from PI3K to TOR. Recent publications have focused on the PI3K-PTEN interactions and on the role of AKT in oncogenic, PI3K-driven signaling. Loss of PTEN has differential effects on PI3K isoforms. The lack of correlation between oncogenic activity of PI3K and signaling through AKT suggests new crosstalks and alternative pathways. PIP₂, phosphoinositide 4,5 bisphosphate; PIP₃, phosphoinositide 3,4,5 trisphosphate; PDK1, phosphoinositide-dependent kinase; TSC1/TSC2, tuberous sclerosis complex; RHEB, RAS homolog enriched in brain.

Figure 2

PI3K and AKT uncoupled. The figure shows examples of non-correlation between PI3K activity and phosphorylation of AKT [15,18].

Figure 3

Involvement of p110β in oncogenesis [30,31]. A. Cultures of mouse embryo fibroblasts (MEF) lacking p110β cannot be transformed by activated RAS. Re-expression of p110β in these cells makes the cultures permissive for RAS-induced transformation. Surprisingly, MEF cultures expressing the catalytically inactive K805R mutant of p110β can also be transformed by RAS, albeit with lower efficiency. B. In a PTEN¯-driven model of prostate cancer, ablation of p110β, but not of p110α prevents tumor formation. In an ERBB2-driven model of breast cancer, substitution of wildtype p110β with the kinase-inactive K805R mutant has a tumor-protective effect.