Emerging Roles for AKT Isoform Preference in Cancer Progression Pathways

Abstract

The phosphoinositol-3 kinase (PI3K)-AKT pathway is one of the most mutated in human cancers, predominantly associated with the loss of the signaling antagonist, PTEN, and to lesser extents, with gain-of-function mutations in PIK3CA (encoding PI3K-p110α) and AKT1. In addition, most oncogenic driver pathways activate PI3K/AKT signaling. Nonetheless, drugs targeting PI3K or AKT have fared poorly against solid tumors in clinical trials as monotherapies, yet some have shown efficacy when combined with inhibitors of other oncogenic drivers, such as receptor tyrosine kinases or nuclear hormone receptors. There is growing evidence that AKT isoforms, AKT1, AKT2, and AKT3, have different, often distinct roles in either promoting or suppressing specific parameters of oncogenic progression, yet few if any isoform-preferred substrates have been characterized. This review will describe recent data showing that the differential activation of AKT isoforms is mediated by complex interplays between PTEN, PI3K isoforms and upstream tyrosine kinases, and that the efficacy of PI3K/AKT inhibitors will likely depend on the successful targeting of specific AKT isoforms and their preferred pathways.

Figure 1:. AKT pathways and mediators.

The activation of PI3K via receptor tyrosine kinases (RTK) or G-protein coupled receptors (GPCR) facilitates AKT-regulated cell growth, proliferation, survival, migration, and metabolisms mediated by the phosphorylation of substrates such as Palladin (PALLD), p21^Waf1 (CDKN1A), S6K (RPS6KB1), FOXO family members or GSK3β. Actuation of maximal AKT serine/threonine kinase activity is mediated by a feedback cycle involving activation of mTORC2 followed by its phosphorylation of AKT on Ser473, and by PDK1 phosphorylation of AKT on Thr308.

Figure 2:. Roles for PI3K and AKT isoforms in specific parameters of oncogenesis.

Specific and sometimes conflicting roles have been attributed to AKT1 or AKT2 in parameters of oncogenic growth, proliferation, survival motility or metabolism. Preferred upstream control of AKT1 or AKT2 is likely controlled PI3K containing p110α or p110β kinase domains, respectively. Though less clarified, several roles for AKT3 in oncogenic progression have been identified recently.