Suppression of insulin feedback enhances the efficacy of PI3K inhibitors

Benjamin Hopkins, Chantal Pauli, Xing Du, Diana Wang, Xiang Li, David Wu, Solomon Amadiume, Marcus Goncalves, Cindy Hodakoski, Mark Lundquist, Rohan Bareja, Yan Ma, Emily Harris, Andrea Sboner, Himsha Beltran, Siddhartha Mukherjee and Lewis Cantley

Nature 2018. 560: 499-503.

Abstract

Mutations in PIK3CA, which encodes the p110 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 cancers1,2. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110? 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 homeostasis3. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy3-6. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness7,8. 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 p110? inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.

Our Thoughts on This Paper

Both glucose homeostasis and the growth of some tumors are PI3K dependent. Because of this inhibitors to the PI3K pathway have been of great interest as targeted therapies, but have had limited effectiveness. In this report, Hopkins et al. show that dramatic and acute hyperglycemia occurs in response to PI3K inhibitors. These elevations in insulin and glucose levels counteract the PI3K inhibition, lessening the effectiveness of these drugs. The authors show that reductions in glucose levels, either by SGLT2 inhibitors are dietary carbohydrate restriction can enhance the efficacy of these drugs in multiple murine ectopic cancer models. This rescue can even be reversed by ‘rescuing’ the reductions in insulin (and glucose levels).

These are striking enhancements in efficacy, and potentially easy to implement in a clinical setting. These data are in line with recent studies showing that genetic hypoinsulinemia or ketogenic diets can lengthen mouse lifespan, likely in part by reducing tumorigenesis (Newman, et al. 2017, Roberts et al. 2017, Templeman, 2017). It is also tempting to speculate whether similar mechanisms underlie reports of fasting improving efficacy of other chemotherapeutics (Buono and Longo, 2018).

These comments were cross-posted at F1000 Prime.

Written by Dave Bridges on Aug. 10, 2018.

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