Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.

Hopkins, Benjamin D; Pauli, Chantal; Du, Xing; Wang, Diana G; Li, Xiang; Wu, David; Amadiume, Solomon C; Goncalves, Marcus D; Hodakoski, Cindy; Lundquist, Mark R; Bareja, Rohan; Ma, Yan; Harris, Emily M; Sboner, Andrea; Beltran, Himisha; Rubin, Mark Andrew; Mukherjee, Siddhartha; Cantley, Lewis C (2018). Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature, 560(7719), pp. 499-503. Macmillan Journals Ltd. 10.1038/s41586-018-0343-4

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Mutations in PIK3CA, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in PTEN, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness. Here we show, in several model tumours in mice, that systemic glucose-insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.

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