Fig. 6

Insulin-Mediated Feedback Loops Following PI3K/mTOR Inhibition: This figure illustrates the complex feedback loops that occur following treatment with PI3K and mTOR inhibitors in cancer cells. When PI3K is inhibited, the liver breaks down stored glycogen, releasing glucose into the bloodstream, resulting in hyperglycemia. The pancreas detects elevated glucose levels, triggering a substantial insulin release, leading to hyperinsulinemia. Hyperinsulinemia partially reactivates the insulin receptor, thereby reinstating the activity of insulin receptor substrate (IRS) and growth factor receptor-bound protein 2 (GRB2). This reactivation leads to an increase in both PI3K and MAPK pathway activation, limiting the therapeutic effects of PI3K inhibitors. Similarly, mTOR1 inhibitors, such as rapamycin, downregulate S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), which blocks downstream translation. The de-repression of 4E-BP1 leads to the enhanced availability of IRS1, acting as an intermediary between the insulin receptor and the PI3K complex. This recruitment of PI3K to the active receptor enhances both MAPK and downstream PI3K signaling, thereby reducing the overall sensitivity to mTOR inhibition. Downregulation of mTOR activity through AKT inhibition or direct mTOR inhibition blocks 4E-BP1-mediated phosphatase and tensin homolog (PTEN) translation. This results in the accumulation of phosphatidylinositol 3,4,5-trisphosphate (PIP3), leading to sustained activation of AKT