The PI3K Pathway in Human Disease

Abstract

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

Oxidative Cyclization‐Induced Activation of a Phosphoinositide 3‐Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics

“…[2] Since the PI3K pathway is frequently deregulated in tumors, it is an attractive target for drug development as both a therapeutic and as an adjunct to improve current treatments. [4] Side effects result from inhibition of normal homeostatic functions of PI3K, such as metabolic, inflammatory, and memory functions. [4] Side effects result from inhibition of normal homeostatic functions of PI3K, such as metabolic, inflammatory, and memory functions.…”

Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors

“…The PI3Kδ inhibitor idelalisib has recently been approved for the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (8,9). In these B cell cancers, PI3Kδ plays an important cell-intrinsic role, but may also affect cells in the tumor microenvironment (10,11). To fully realize the potential of PI3Kδ inhibitors and for the optimal design of patient stratification and combinatorial therapies, it is imperative to further elucidate the impact of PI3Kδ inhibition on tumor immunity.…”

PI3‐kinase pathway biomarkers in oral cancer and tumor immune cells

“…29 In tumor associated macrophages, the PI3-kinase catalytic isoform p110-γ promotes an immunosuppressive phenotype characterized by upregulation of interleaukin 10 (IL-10) and transforming growth factor-β (TGF-β). 1 Our study was not designed to characterize the status of the PI3-kinase pathway activation on the subpopulations of the immune cells. 30,31 Participation of the Abbreviations: Akt = Protein Kinase B; CI = confidence interval); mTOR = mammalian target of rapamycin; N/A = not applicable); OS = overall survival; p-Akt = phosphorylated Akt; p-mTOR = phosphorylated mammalian target of rapamycin; PTEN = phosphatase and tensin homolog; RFS = recurrence-free survival PI3-kinase pathway in the process of adaptive immunity includes downstream signaling after T-cell receptor engagement and activation by costimulatory molecules, 27 proliferation of T regulatory cells, 32 and control of CD8-positive T cell fate.…”

“…1 Phosphoinositide 3-kinase (PI3-kinase) is one of the most commonly mutated and/or amplified genes in head and neck squamous cell carcinomas. In humans, 4 class I catalytic isoforms of PI3kinase have been described (p110-α, p110-β, p110-γ, and p110-δ, the former 2 ubiquitously expressed and the latter 2 enriched in immune cells).…”