Phosphoinositide 3-kinase inhibition in cancer treatment

Abstract

Over the past ten years, our knowledge of the integral role that the phospho-inositide 3-kinases (PI3Ks) and their 3'-phosphorylated lipid products (3'-phosphorylated phosphoinositides; 3P-PIs) play in the mediation of signal transduction, cytoskeletal rearrangements and membrane trafficking has expanded considerably. They are now known to be involved in the regulation of cell growth, differentiation, mobility, proliferation and survival and hence they have become a potential target for the control of the growth and spread of cancer cells. More recently, the correlation of the multiplicity of isomers (both catalytic and regulatory) within the different classes of the PI3Ks with their functional relevance has become possible. This, combined with our further understanding of the protein recognition patterns for their different 3P-PIs and the newly-described pathways in the control of the levels of these by dephosphorylation, has provided new aspects and areas for interference in these multiple PI3K signalling pathways. However, in the search for effective, non-toxic, drugs for use in the treatment of cancers, these individual targets for PI3K inhibition need to be further correlated with the specific in vivo effects on cell survival, invasivity and metastatic potential. Here, the range of PI3K inhibition targets are discussed in the light of recent experimental findings, with a view to the exploitation of their specificities in new approaches to effective cancer treatments based on PI3K activity inhibition.