Defining Feedback Loops Between Phosphoinositide 3-kinases (PI3Ks) Isoforms and Insulin to Harness the Full Potential of PI3K-Targeted Therapies

Class-1 phosphoinositide 3 kinases (PI3K) play a central role in the transduction of growth factors and insulin signals, and PI3K activity maintains tissue and metabolic homeostasis. Activation of PI3K signaling is the most frequent alteration in cancer and plays a major role in tumor progression.

However, on-target adverse effects on insulin signaling driving systemic metabolic feedback loops conferring tumor resistance to PI3K inhibition dampens the efficacy of PI3K-targeted therapies.

Indeed, inhibition of all PI3K isoforms causes severe hyperglycemia and hyperinsulinemia, which induces PI3K activity in the tumor, causing resistance to PI3K inhibitors (PI3Ki). Thus, avoiding hyperinsulinemia is key to harnessing the full therapeutic potential of PI3Ki.

There are four PI3K: PI3Kα; PI3Kβ; PI3Kγ; and PI3Kδ, and insulin signaling was believed to depend on PI3Kα, the most frequently mutated PI3K in cancer. However, we have found that insulin signaling in the hepatocyte is mediated by redundant PI3Kα and PI3Kβ activities.

Furthermore, our data indicate that PI3K activity in the adipose tissue plays a potent role in PI3Ki-driven hyperinsulinemia.This proposal aims to identify how PI3K signaling controls insulin secretion.

This knowledge is fundamental to the develop isoform-selective PI3Ki, which do cause hyperinsulinemia, to exploit the full therapeutic potential of PI3K-targeted therapy.