Developing Biomarkers for PI3K-targeted Cancer Therapies

Phosphatidylinositol 3-kinases (PI3Ks) are intracellular lipid kinases that phosphorylate the 3'-hydroxyl group of the inositol ring in phosphatidylinositol and phosphoinositides. In response to growth factors, cytokines or other environmental cues, PI3Ks generate lipid second messengers that create binding sites for specific lipid-binding domains on many intracellular signaling proteins and thereby regulate a variety of cellular processes, including cell cycle progression, cell survival, growth, migration, and vesicular trafficking [1, 2]. Hyper activation of PI3K signaling is one of the most common features of many human cancers [2, 3], making this class of enzymes a prime drug target. Tremendous efforts have been made to develop effective PI3K inhibitors for cancer therapy, including both pan-PI3K inhibitors and isoform-selective PI3K inhibitors. A significant need has emerged for analytically validated and clinically qualified biomarkers that can assess the pharmacodynamic effects of the drug, guide patient selection, and understand mechanisms of resistance.