Molecular Pathways: Targeting Phosphoinositide 3-Kinase p110-Delta in Chronic Lymphocytic Leukemia

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 p110 delta isoform (which is localized to hematopoietic cells and regulates distinct cellular functions in B cells). In addition, the clinical advances from targeting p110 delta are described, with a focus on clinical outcome, toxicities, and rational combination therapies. The experiences with p110 delta in CLL have led to a more fundamental understanding of CLL signaling defects and may be predictive of other BCR-directed therapeutics. Clin Cancer Res; 18(15); 4013-8. (C)2012 AACR.