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).
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.
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