Fig. 5

The figure illustrates the molecular contexts that determine the applications of isoform-selective PI3K inhibitors. It represents different molecular alterations and their effects on PtdIns(3,4,5)P3 production through specific PI3K isoforms. A Upregulation or mutation of receptor tyrosine kinases (RTKs), oncogenic RAS mutations, or activating p110α mutations result in increased PtdIns(3,4,5)P3 production through p110α, which can be further amplified by mutation or loss of PTEN. In these contexts, the use of p110α-selective inhibitors is effective. B In the absence of other oncogenic alterations, loss or mutation of PTEN increases PtdIns(3,4,5)P3 production through p110β, potentially due to RAC1- or CDC42-mediated p110β activation or the basal activity of this isoform. In this context, the use of p110β-selective inhibitors is effective. C Upregulation or mutation of B cell receptors (BCRs), cytokine receptors, or other immune cell surface markers leads to increased PtdIns(3,4,5)P3 production through p110δ. In this context, the use of p110δ-selective inhibitors is effective. These different molecular alterations and their specific effects on PI3K isoforms highlight the rationale for using isoform-selective PI3K inhibitors based on the molecular context of the disease. This knowledge can guide the development and application of targeted therapies for various contexts associated with PI3K pathway dysregulation