Background

PI3Ks are a family of evolutionary conserved enzymes composed of 3 classes and present in all eukaryotic organisms. They phosphorylate the 3-position of phosphatidylinositol, a minor membrane phospholipid. 3-phosphorylated lipids serve as tags for intracellular proteins involved in signal transduction, membrane dynamics and cell motility. Mammals express 8 catalytic isoforms divided in 3 classes of PI3Ks; 4 class I PI3Ks, 3 class II PI3Ks and 1 class III PI3Ks.

The class I PI3K isoforms in the clinic – The class I PI3Ks (p110α, p110β, p110γ and p110δ) phosphorylate PtdIns(4,5)P2 to generate the second-messenger signalling molecule PtdIns(3,4,5)P3. Class I is hyper-activated in many disease processes and, hence, small molecule inhibitors against different class I PI3K isoforms are being evaluated in more than 100 clinical studies. p110α and p110β are broadly expressed whereas the expression of p110δ and p110γ is more limited to haematopoietic cells. The gene encoding p110α is amongst the most frequently mutated genes in human cancers. Pten encodes a lipid phosphatase that antagonises PI3K signalling and is also frequently mutated or lost in human cancers. Thus many clinical trials aim at the specific inhibition of p110α or PI3Ks in general. The first PI3K inhibitor to be approved for clinical use is a p110δ–selective inhibitor, which has shown high efficacy in phase III clinical trials for B cell lymphoma. There is also rising interest in using p110δ and/or p110γ inhibitors to alleviate autoimmune and inflammatory diseases. Thus, our knowledge of class I PI3Ks is at a relatively advanced stage and is being exploited for the benefit of patients. However, the use of PI3K inhibitors in humans has turned out to be more challenging than anticipated; in many cases the benefits appear to be transient. These observations highlight the need for a better understanding of the biology of PI3K isoforms to develop future generations of PI3K inhibitors for use in oncology and inflammation that overcome resistance development and on-target side effects.

The enigmatic class II and class III PI3Ks – Little is known about class II (C2α, C2β and C2γ) and III (Vps34) PI3Ks in mammalian cells and how these can be exploited for drug development. Class II and III PI3K enzymes have been implicated in intracellular membrane dynamics with potential involvement in immunity and inflammation, neurodegeneration and cancer. Class II and class III phosphorylate PtdIns, and the myotubularin family of phosphatases (mammals have 14 members), dephosphorylate PI3P and possibly PtdIns(3,5)P2. Loss of myotybularin results in myopathy disease in humans. Network participants are at the forefront of this research area and are poised to develop new drugs for congenital myopathies and beyond.