Cited by 708PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerCancer, Hypoxia, and Metabolism

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Suppression of insulin feedback enhances the efficacy of PI3K inhibitors

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Hopkins, Benjamin D., Pauli, Chantal, Du, Xing, Wang, Diana G., Li, Xiang, Wu, David, Amadiume, Solomon C., Goncalves, Marcus D., Hodakoski, Cindy, Lundquist, Mark R., Bareja, Rohan, Ma, Yan, Harris, Emily M., Sboner, Andrea, Beltran, Himisha, Rubin, Mark A., Mukherjee, Siddhartha, Cantley, Lewis C.·2018·Nature

DOI 10.1038/s41586-018-0343-4PMC PMC6197057

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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 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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Additional file 5 of Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells
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Additional file 2 of DNMT1-targeting remodeling global DNA hypomethylation for enhanced tumor suppression and circumvented toxicity in oral squamous cell carcinoma
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Additional file 6 of Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells
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Additional file 4 of Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells
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Additional file 1 of Loss of hexokinase 1 sensitizes ovarian cancer to high-dose metformin
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Additional file 3 of Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells
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Additional file 1 of Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity
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Additional file 1 of Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells
Theodossiou, S. K., Murray, J. B., Hold, L. A., Courtright, J. M., Carper, A. M., & Schiele, N. R. (2021) · Figshare · doi:10.6084/m9.figshare.13647053
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Additional file 2 of Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells
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“Because of the role of PI3K in glucose uptake and metabolism, PI3K inhibitors raise blood glucose levels, which leads to increased pancreatic insulin production and elevated blood insulin levels (19, 20).”

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: Hopkins, Benjamin D.
Pauli, Chantal
Du, Xing
Wang, Diana G.
Li, Xiang
Wu, David
Goncalves, Marcus D.
Lundquist, Mark R.
Bareja, Rohan
Ma, Yan
Harris, Emily M.
Sboner, Andrea
Beltran, Himisha
Rubin, Mark A.
Mukherjee, Siddhartha
Cantley, Lewis C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-07-04
Volume: 560
Issue: 7719
Pages: 499-503
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0343-4
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: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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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Suppression of insulin feedback enhances the efficacy of PI3K inhibitors

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