Molecular pathways: targeting phosphoinositide 3-kinase p110-delta in chronic lymphocytic leukemia

Abstract

The advent of targeted therapy, specifically to the B-cell receptor (BCR), has changed the convention for the treatment of chronic lymphocytic leukemia (CLL). The phosphoinositide 3-kinase (PI3K) pathway, activated upstream by the BCR, receptor tyrosine kinases, and cytokine receptors, has been a potential target for a multitude of cancers, but until the recent introduction of isoform-specific inhibitors has not been widely used. In this review, we focus on describing the intricate upstream and downstream signaling, leading to cell survival mediated by PI3K in B cells with a specific focus on the impact and importance of the p110δ isoform (which is localized to hematopoietic cells and regulates distinct cellular functions in B cells). In addition, the clinical advances from targeting p110δ are described, with a focus on clinical outcome, toxicities, and rational combination therapies. The experiences with p110δ in CLL have led to a more fundamental understanding of CLL signaling defects and may be predictive of other BCR-directed therapeutics.

Figure 1

Phosphoinositide 3-kinase (PI3K) signaling can be activated via a variety of methods including stimulation from the microenvironment leading to engagement of the B-cell receptor (BCR), cytokine receptors or receptor tyrosine kinases. Upon receptor activation, accessory molecules lead to the activation of PI3K. All three class 1A isoforms of PI3K (p110α, p110β and p110δ), facilitate the phosphorylation of phosphatidylinositol (3,4)-biphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3), leading to the phosphorylation of downstream signaling molecules. GS-1101, a selective p110δ isoform inhibitor, thereby prevents the activity of PI3K and thus inhibits the phosphorylation of downstream kinases; the hallmark of which is AKT. By preventing the phosphorylation of AKT, GS-1101 alters cell homeostasis by: 1) preventing the phosphorylation of GSK3◻ thereby preventing the transcription of survival genes induced by intact -catenin, 2) preventing the phosphorylation of caspase 9 leaving its protease activity intact and allowing for activation of the intrinsic caspase cascade, 3) preventing the phosphorylation of Frhl1 which blocks the binding of 14-3-3 allowing Frkh1 to translocate to the nucleus and transcribe genes related to cell death (such as FASL), and 4) preventing the phosphorylation of the IKK complex which inhibits its ability to phosphorylate IKBα preventing the release of the NF-κB complex and translocation to the nucleus; thereby again preventing survival gene transcription. Thus, inhibition of p110δ by GS-1101 tips the signaling balance from cell survival to cell death.