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Suppression of insulin feedback enhances the efficacy of PI3K inhibitors
Open accessAbstract
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 1,2. 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 3. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy 3-6. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K-mTOR signalling axis in tumours, thereby compromising treatment effectiveness 7,8. 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 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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“Placing mice on a low-carbohydrate, ketogenic diet blunts the hyperglycemia and insulin release that accompany PI3K inhibition, and this improves the efficacy of PI3K inhibitors on tumor growth (113).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [113]
In the citing paper
“PI3K inhibitors suppress glucose uptake by the muscle and other tissues, resulting in elevated blood glucose and pancreatic insulin release after administration of the drug. The insulin surge reactivates PI3K signaling in the tumor, limiting the efficacy of PI3K inhibitors on tumor growth.”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [113]
In the citing paper
“Therefore, the direct use of specific diets, or the modulation of inter‐organ communication, could have a pharmacological effect on its own 167 or increase the efficiency of pharmacological approaches to treat a wide variety of diseases 173, 174.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [173]
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“ing insulin feedback and in turn, enhancing the efficacy and reduce the toxicity of PI3K inhibitors.(36,40) These”
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“They found that the use of PI3K inhibitors in conjunction with a ketogenic diet inhibited the insulin feedback-induced activation of the mTORC1 pathway by lowering insulin levels, thereby enhancing the efficacy of PI3K inhibitors, resulting in an anti-tumor effect (40).”
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“Similar to the activation of PI3K/AKT/mTOR signaling is also attenuated by feedback inhibition through a series of AKT- or mTOR-dependent mechanisms [36,37].”
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Alpelisib-Induced Diabetic Ketoacidosis
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“Smaller tumor volumes may be achieved by reducing insulin levels, thereby decreasing insulin’s ability to activate insulin receptors in tumors [8].”
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“It is also shown that KD can improve the response of PI3K inhibitor BKM120 in MLL-AF9 AML mouse model (14).”
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“Placing tumour-bearing mice on a ketogenic diet prevented the induction of insulin secretion and enhanced the antitumour effect of the inhibitor (Hopkins et al., 2018).”
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Metadata
- Authors
- Hopkins, B. D., Pauli, C., Du, X., Wang, D. G., Li, X., Wu, D., Amadiume, S. C., Goncalves, M. D., Hodakoski, C., Lundquist, M. R., Bareja, R., Ma, Y., Harris, E. M., Sboner, A., Beltran, H., Rubin, M. A., Mukherjee, S., & Cantley, L. C.
- Affiliations
- Weill Cornell Medicine (US)
- NewYork–Presbyterian Hospital (US)
- University of Bern (CH)
- Corresponding author
- Mukherjee, Siddhartha
- Cantley, Lewis C.
- ORCID
- Venue
- Nature
- Published
- 2018-07-04
- Volume
- 560
- Issue
- 7719
- Pages
- 499-503
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6197057
- OpenAlex
- W2809999132
- Cited by
- 706
- References
- 29
- Citations by year
- 2026: 54 · 2025: 88 · 2024: 101 · 2023: 79 · 2022: 98 · 2021: 128 · 2020: 70 · 2019: 74 · 2018: 14
- FWCI
- 25.30
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-08-29)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, other-oa)
- Funders
- Breast Cancer Research Foundation (P30CA013696, R01 GM041890)
- Memorial Sloan-Kettering Cancer Center
- Gray Foundation
- National Institutes of Health (U54 U54CA210184, GM041890)
- National Cancer Institute (U54CA210184, R35CA197588, P01CA117969, P30CA013696)
- National Institute of General Medical Sciences (R01GM041890)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- PI3K inhibitors, PIK3CA, PTEN, p110α, hyperglycemia, insulin resistance, cancer therapy resistance, tumor glucose metabolism
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Blood Glucose, Cell Survival, Disease Models, Animal, Insulin, Male, Mice, Inbred C57BL, Mice, Nude, Neoplasms, Signal Transduction, Feedback, Physiological, Protein Kinase Inhibitors, Cell Proliferation, Mice, TOR Serine-Threonine Kinases
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