AKT in cancer: new molecular insights and advances in drug development

Abstract

The phosphatidylinositol-3 kinase (PI3K)-AKT pathway is one of the most commonly dysregulated pathways in all of cancer, with somatic mutations, copy number alterations, aberrant epigenetic regulation and increased expression in a number of cancers. The carefully maintained homeostatic balance of cell division and growth on one hand, and programmed cell death on the other, is universally disturbed in tumorigenesis, and downstream effectors of the PI3K-AKT pathway play an important role in this disturbance. With a wide array of downstream effectors involved in cell survival and proliferation, the well-characterized direct interactions of AKT make it a highly attractive yet elusive target for cancer therapy. Here, we review the salient features of this pathway, evidence of its role in promoting tumorigenesis and recent progress in the development of therapeutic agents that target AKT.

Keywords: clinical oncology; medical oncology; phosphatidylinositol 3-kinases; protein kinase B; proto-oncogene proteins c-AKT; proto-oncogene proteins c-AKT/genetics; proto-oncogene proteins c-AKT/metabolism; proto-oncogene proteins c-AKT/physiology; signal transduction/physiology.

Figure 1

The phosphatidylinositol‐3 kinase (PI3K)–AKT PI3K‐AKT pathway is activated upstream by ligand binding to a growth factor receptor, in this case a receptor tyrosine kinase (RTK). Activated phosphotyrosine residues of the RTK interact with src‐homology 2 (SH2) domains on PI3K, as well as other SH2‐containing proteins. This leads to generation of the important lipid second messenger phosphatidylinositol 3,4,5‐trisphosphate (PIP3). AKT localizes to the cell membrane through interactions of its pleckstrin homology (PH) domain with PIP3, which ultimately leads to phosphorylation and activation of AKT by phosphoinositide‐dependent kinase (PDK) 1 and PDK2. AKT activates and inhibits a number of effector proteins via phosphorylation, including mammalian target of rapamycin (mTOR), IκB kinase (IKK), mouse double minute 2 homolog (Mdm2), Bad, p27, glycogen synthase kinase‐3 (GSK3) and forkhead family of transcription factors (FOXO) 1,4. The net result is increased cell survival and proliferation. P, phosphate; PIP2, phosphatidylinositol 4,5‐bisphosphate; PTEN, phosphatase and tensin homologue deleted on chromosome 10

Figure 2

AKT1, AKT2 and AKT3 share common domain architecture with other members of the cAMP‐dependent, cGMP‐dependent and protein kinase C (AGC) subfamily of protein kinases, which consists of an N‐terminus pleckstrin homology (PH) domain, a large central kinase domain and a C‐terminus hydrophobic domain (HD). The position of threonine and serine residues involved in phosphorylation varies only slightly between the three different isoforms

Figure 3

A selection of downstream targets of AKT is displayed. Following upstream activation, in this case by insulin‐like growth factor receptor 1 (IGF‐1R) signalling, AKT phosphorylates and inactivates three key downstream effectors: glycogen synthase kinase‐3 beta (GSK3B), tuberous sclerosis 1 and 2 (TSC1/2) and the proapotosis proteins caspase 9 and Bad. Inhibition of TSC1/2 leads to subsequent inhibition of Ras homologue enriched in brain (Rheb) and the downstream conversion of mammalian target of rapamycin (mTORC) 2 to mTORC1. This ultimately leads to the phosphorylation of p70S6 kinase and 4E‐BP1, which favours an increase in ribosomal protein translation and cell growth. Phosphorylated p70S6 kinase normally exerts negative feedback by inhibiting IGF‐1R signalling; loss of this negative feedback loop occurs in cancer cells following treatment with mTOR inhibitors. GBL, G protein beta protein subunit‐like