Suppression of insulin feedback enhances the efficacy of PI3K inhibitors.

TitleSuppression of insulin feedback enhances the efficacy of PI3K inhibitors.
Publication TypeJournal Article
Year of Publication2018
AuthorsHopkins BD, Pauli C, Du X, Wang DG, Li X, Wu D, Amadiume SC, Goncalves MD, Hodakoski C, Lundquist MR, Bareja R, Ma Y, Harris EM, Sboner A, Beltran H, Rubin MA, Mukherjee S, Cantley LC
JournalNature
Volume560
Issue7719
Pagination499-503
Date Published2018 08
ISSN1476-4687
KeywordsAnimals, Blood Glucose, Cell Proliferation, Cell Survival, Disease Models, Animal, Feedback, Physiological, Insulin, Male, Mice, Mice, Inbred C57BL, Mice, Nude, Neoplasms, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors, Signal Transduction, TOR Serine-Threonine Kinases
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.

DOI10.1038/s41586-018-0343-4
Alternate JournalNature
PubMed ID30051890
PubMed Central IDPMC6197057
Grant ListP01 CA117969 / CA / NCI NIH HHS / United States
U54 CA210184 / CA / NCI NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States
R35 CA197588 / CA / NCI NIH HHS / United States
P30 CA013696 / CA / NCI NIH HHS / United States

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