Abstract
The drug Idelalisib is the first PI3K inhibitor to be approved by the FDA for clinical use. It is therefore timely to take stock of our current understanding of the role of PI3Ks in the immune system. The phosphoinositide 3-kinases (PI3Ks) control many key functions in immune cells (1). PI3Ks phosphorylate PtdIns(4,5)P2 to yield PtdIns(3,4,5)P3, which acts as a second messenger signaling molecule that controls the activation of Akt and other proteins with PH domains. Initially, PI3K inhibitors such as Wortmannin, LY294002, and Rapamycin were used to establish a central role for PI3K pathway in immune cells. More recent progress in understanding the role of this pathway in cells of the immune system has been made through the generation of wide range of gene-targeted mouse models as well as with the development of highly selective small molecule inhibitors, culminating in the FDA approval of the PI3Kδ inhibitor Idelalisib in 2014. Together, lab experiments, preclinical, and clinical trials have revealed how PI3Ks control B cell and T cell development, T helper cell differentiation, regulatory T cell (Treg) development and function, B cell and T cell trafficking, immunoglobulin class switching, and much more.
Highlights
MTOR inhibitors such as rapamycin are already established as among the most commonly used drugs to prevent transplant rejection and are increasingly evaluated for the use in cancer [3]
Many other phosphoinositide 3-kinases (PI3Ks) inhibitors are going through clinical trials with the aim to treat cancers, and inflammatory and autoimmune diseases
Limon and Fruman review the role of PI3Ks in B cell development and activation and consider how the related Akt, Foxo, and mTOR pathways affect B cell biology [6]
Summary
MTOR inhibitors such as rapamycin are already established as among the most commonly used drugs to prevent transplant rejection and are increasingly evaluated for the use in cancer [3]. The PI3Kδ-selective inhibitor Idelalisib (CAL-101) has received FDA approval for the treatment of chronic lymphocyte leukemia and indolent non-Hodgkin’s lymphoma following on from successful clinical trials showing dramatic improvements in progress-free survival [4, 5]. This eBook contains 11 chapters that cover different roles of the PI3K and mTOR pathways, primarily in B cells and T cells.
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