Should individual PI3 kinase isoforms be targeted in cancer?

Abstract

Activation of the phosphoinositide-3-kinase (PI3K) signaling pathway is frequently found in common human cancers, brought about by oncogenic receptor tyrosine kinases (RTKs) acting upstream, PTEN loss, or activating mutations of PI3K itself. Recent studies have delineated distinct but overlapping functions in cell signaling and tumorigenesis for p110alpha and p110beta, the two major catalytic subunits of PI3K expressed in the tissues of origin for the common tumor types. In most cell types studied, p110alpha carries the majority of the PI3K signal in classic RTK signal transduction, while p110beta responds to GPCRs. Both p110alpha and p110beta function in cellular transformation induced by alterations in components of PI3K pathway. Specifically, p110alpha is essential for the signaling and growth of tumors driven by PIK3CA mutations and/or oncogenic RTKs/Ras, whereas p110beta is the major isoform in mediating PTEN-deficient tumorigenesis. While pan-PI3K inhibitors are currently being tested in the clinic, p110 isoform-specific inhibition holds promise as a therapeutic strategy.

Figure 1

Distinct roles for p110α and p110β in signaling. p110α appears to the major effector in classic RTK signaling whereas p110β responds to GPCRs. In a cell with equal amounts of the two enzymes, p110α carries the majority of the PI3K signal upon stimulation by EGF and IGF/insulin. Stronger signals such as PDGF are able to saturate AKT by activating either p110α or p110β. EGF, epidermal growth factor; IGF, insulin-like growth factor; PDGF, platelet-derived growth factor.

Figure 2

p110 isoform-specific inhibition in treating tumors driven by oncogenic RTKs and Ras. Inhibitors of p110α and p110β will help block tumorigenesis induced by oncogenic RTKs (left part). A p110α-specific inhibitor will be useful to tumors driven by p110α mutants (not shown) and Ras (right part).

Figure 3

p110 isoform-specific inhibition in treating PTEN-deficient tumors. In a given tumor driven by PTEN loss, the p110 isoform dependence may be determined by input signals which are amplified by loss of PTEN. If these signals arise from a GPCR, then p110β will be the major isoform carrying the load. When the signals activating the PI3K pathway come from coexisting oncogenic components e.g. RTKs, Ras or activating mutants of p110α (*RTKs, *Ras, *p110α), then p110α takes command.