Suppression of insulin feedback enhances the efficacy of PI3K inhibitors

Abstract

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.

Exploring Biomarkers of Phosphoinositide 3-Kinase Pathway Activation in the Treatment of Hormone Receptor Positive, Human Epidermal Growth Receptor 2 Negative Advanced Breast Cancer

“…Furthermore, a dose‐dependent increase in the plasma levels of fasting C‐peptide and insulin, frequently associated with hyperglycemia, is an obligatory on‐target pharmacodynamic surrogate of PI3K inhibition in trials with PI3K inhibitors . This obligatory surge in insulin secretion may activate insulin receptors and PI3K, particularly in tumors rich in insulin receptors, and limit the clinical activity of PI3K inhibitors . Therefore, future development of inhibitors with greater selectivity for p110α mutant isoforms and reduced inhibitory activity against wild‐type p110α protein is sorely needed to further advance the field.

Although the addition of PI3K inhibitors to ET has demonstrated modest clinical responses, the magnitude of benefit observed thus far has been below that initially expected.

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Lysosome: The metabolic signaling hub

“…While the utility of rapamycin in a handful disorders is clear, its overall success in preventing cancer growth remains poor. Whether this is due to an incomplete understanding of mTORC1’s requirement for rapid cell proliferation, the ability of cancers to acquire rapamycin-resistance 196 , the reactivation of PI3K signaling due to systemic glucose-insulin feedback on most diets 197 , or its mechanism of action as an allosteric inhibitor that blocks the phosphorylation of only some of the mTORC1 substrates, remains to be seen. However, there is a palpable excitement that the new generation of therapeutic agents targeting metabolic signaling at the lysosome will have substantial benefits for human health.…”

Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

“…Consistent with this observation, we observed hyperinsulinemia in 64% of patients treated in our study. It is important to underscore that in these models, strong suppression of the insulin feedback loop had the potential to increase PI3K inhibitor efficacy . Thus, combining PI3K pathway inhibitors with interventions that lower circulating insulin may be a promising strategy to improve efficacy in patients.…”

“…For example, the high rate of PTEN alterations, which preferentially signal through PI3Kβ, suggest that isoform‐selective PI3K inhibitors, which have been successful in the context of PIK3CA ‐mutant breast cancer, are unlikely to be efficacious in this setting . In addition, intricate feedback loops can activate compensatory signaling pathways, which may contribute to the lack of efficacy of agents that selectively target terminal components of the pathway, such as mTOR . There is evidence suggesting that dual PI3K and mTOR inhibition may more potently inhibit the PI3K signaling pathway and provide a more efficient pathway blockade …”

“…16,17 In addition, intricate feedback loops can activate compensatory signaling pathways, which may contribute to the lack of efficacy of agents that selectively target terminal components of the pathway, such as mTOR. 18,19 There is evidence suggesting that dual PI3K and mTOR inhibition may more potently inhibit the PI3K signaling pathway and provide a more efficient pathway blockade. 20 LY3023414 is a novel selective inhibitor of class I PI3K isoforms, mTORC1/2, and DNA-PK (DNAdependent protein kinase).…”