Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs

Abstract

It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.

Figure 1. The PI3K/Akt/mTOR signaling pathway and associated inhibitors

A ligand engaged RTK binds PI3K, either directly or indirectly via adaptor molecules such as IRS1, removing the inhibitory action of the p85 regulatory subunit on the catalytic p110 subunit. The active kinase generates PIP3 at the lipid membrane. PIP3 facilitates the phosphorylation of Akt by PDK1, while the mTOR-rictor complex contributes a second phosphate residue to Akt. As the central effector of the PI3K pathway, Akt transmits signal to a host of downstream substrates, thus influencing a variety of key cellular functions. Pathway activity is negatively regulated by PTEN and the S6K-IRS1 feedback loop. Pharmacological inhibition of the pathway is achieved through a variety of compounds in clinical use at various points along the pathway that are indicated by the red ⊣.