Fig. 1.

Schematic representation of the PI3K/mTOR signalling pathway with pharmacological agents in pre-clinical/clinical development for CLL indicated. (A) PI3K activation by receptor ligation induces re-localisation and activation of AKT (amongst other proteins not shown) which in turn initiates downstream signalling events crucial for CLL survival and proliferation. PI3K inhibitors in pre-clinical development, clinical trials or approved for CLL treatment are indicted. mTOR exists in two complexes; mTORC1 which phosphorylates S6 kinase and 4E-BP1 (eukaryotic translation initiation factor 4E-binding proteins) thereby promoting translation and protein synthesis and mTORC2 which phosphorylates and thus enhances the activation of AKT. (B) S6 kinase is activated downstream of PI3K and mTORC1 and promotes ribosomal translational activity. S6 kinase also acts in a negative feedback loop to constrain further PI3K mediated signalling. Selective inhibition of mTORC1 (for example by everolimus as indicated) abrogates S6 kinase mediated negative feedback mechanisms and leads to enhancement of PI3K mediated signalling and AKT activation. This effect is thought to have limited the efficacy of mTOR inhibitors alone in the clinic for various cancers. Use of a dual PI3K/mTOR inhibitor (for example PF-04691502 as indicated) prevents this amplification of PI3K signalling by preventing the phosphorylation of AKT by mTORC2 and by directly inhibiting PI3K.