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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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“Moreover, one recent preclinical study indicated that PI3K inhibitor-induced increase of serum insulin concentration in patients with cancer might be sufficient to reactivate the PI3K/AKT/mTORC1 pathway, thus resulting in resistance to PI3K inhibition in HRþ/HER2 breast cancer cell lines and murine models (19).”
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“4 prevent, attenuate, or reduce the morbidity of this drug-induced hyperglycemia.([14]) In short, this study provides evidence of feasibility that dietary modification – and specifically a ketogenic diet – merits further testing in clinical trials aimed at making cancer treatment as well as perhaps other health issues…”
BackgroundLoss of hexokinase 1 sensitizes ovarian cancer to high-dose metformin
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“In addition, GLUT-4 is the terminal signal of intracellular insulin signal transduction [34, 35].”
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“However, it has been demonstrated that this glucose – insulin feedback to treatment reactivates PI3K/AktsignalingeveninthepresenceofaPI3Kinhibitor 38 – 40 .”
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“Study results demonstrated that resistance to PI3K inhibitors is mediated through reactivation of the PI3K-mTOR signaling pathway by insulin feedback (32).”
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“Other studies have described that KD increase the efficacy of targeted therapies, in particular the use of PI3K inhibitors, and helps in the treatment when resistance to drugs arises (31).”
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“Due to its mechanism of action, there is some concern that insulin and secretagogues may attenuate the anticancer effect of PI3K inhibitors.(30,31) While this effect has not been addressed in large clinical trials and is hypothetical to date, it is further incentive to look at agents other than insulin and secretagogu…”
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“In this context, KD can in fl uence tumor cell growth by lowering insulin and insulin-like growth factor-1 (IGF-1) levels, thus reducing one of the most common oncogenic pathways such as PI3K-Akt-mTOR implicated in tumor cell proliferation and tumor growth (34, 35).”
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Just a spoonful of metformin helps the medicine go down
Tzaridis, T., & Wechsler‐Reya, R. J. (2024) · Journal of Clinical Investigation · doi:10.1172/jci179144 · Cited by 6
“…at a dose of 200 mg/ kg (15), slightly higher than the dose used in Duchatel and Jackson et al. In addition, Noch and colleagues also fed mice a ketogenic diet, an intervention known to reduce hepatic glycogen stores, potentially limiting the release of glucose following PI3K inhibition (15, 16).”
Diet predisposes to pancreatic cancer through cellular nutrient sensing pathways
Noè, R., & Carrer, A. (2024) · FEBS Letters · doi:10.1002/1873-3468.14959 · Cited by 7
Non-coding transcriptome profiles in clear-cell renal cell carcinoma
Tesařová, T., Fiala, O., Hora, M., & Václavíková, R. (2024) · Nature Reviews Urology · doi:10.1038/s41585-024-00926-3 · Cited by 6
“However, the efficacy of these inhibitors seems to be limited, possibly owing to increased glucose concentrations leading to insulin release, which overcomes this inhibition 65 .”
Hyperglycemia secondary to phosphatidylinositol-3 kinase (PI3K) inhibition
Sriravindrarajah, A., Hurwitz, J., Lim, E., & Greenfield, J. R. (2024) · Endocrinology Diabetes and Metabolism Case Reports · doi:10.1530/edm-24-0040 · Cited by 6
Arming Immune Cell Therapeutics with Polymeric Prodrugs
López, C. L., Brempelis, K. J., Matthaei, J. F., Montgomery, K. S., Srinivasan, S., Roy, D., Huang, F., Kreuser, S. A., Gardell, J. L., Blumenthal, I., et al. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202101944 · Cited by 6
Ohyama, K., Tanaka, H., & Hori, Y. (2022) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/jpps32908 · Cited by 6
Cramer, T. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101736 · Cited by 6
Li, X., Cheng, Y., Xu, Z., Lin, X., Xu, B., Wang, Z., Li, P., & Nian, B. (2024) · Food Research International · doi:10.1016/j.foodres.2024.114059 · Cited by 6
Self-citationBibliometric analysis of PTEN in neurodevelopment and neurodegeneration
Zhang, Y., Tan, Y.-T., Wang, M., Li, L., Huang, J.-F., & Wang, S. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1390324 · Cited by 6
Charlot, A., Conrad, O., & Zoll, J. (2020) · Biologie Aujourd hui · doi:10.1051/jbio/2020014 · Cited by 6
Modifying dietary amino acids in cancer patients
Connolly-Schoonen, J., Biamonte, S. F., Danowski, L., & Montrose, D. C. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.02.004 · Cited by 6
Wang, X., Wang, Z., Liu, Z., Huang, F., Pan, Z., Zhang, Z., & Liu, T. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189322 · Cited by 5
Bejugam, D., Bu, S., Nguyen, A. N., Yaltaghian, M., & Smolen, K. K. (2025) · Frontiers in Clinical Diabetes and Healthcare · doi:10.3389/fcdhc.2025.1586061 · Cited by 5
β-Hydroxybutyrate promotes chemoresistance and proliferation in breast cancer cells
Mashinchian, M., Vandghanooni, S., Karamibonari, A. R., & Eskandani, M. (2025) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2025.102217 · Cited by 5
“Furthermore, KD lowers insulin and insulin-like growth factor (IGF-1) levels, which are known to increase cancer cell proliferation and survival [27].”
From PIK3CA Mutations to Rational PI3K Inhibition for the Treatment of Colorectal Cancer
Voutsadakis, I. A. (2025) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-025-00815-4 · Cited by 5
“However, in tumor cells, increased levels of insulin promote signaling through the PI3K/AKT transduction pathway and resistance to inhibitors of the pathway [64].”
Alpelisib-Induced Diabetic Ketoacidosis and Insulin-Resistant Hyperglycemia
Loke, M., Sehgal, V., & Gupta, N. (2024) · AACE Clinical Case Reports · doi:10.1016/j.aace.2024.10.002 · Cited by 7
Lipid droplets and autophagosomes together with chaperones fine‐tune expression of SGK1
Ghani, M. J., Gu, W., Chen, Z., & Canessa, C. M. (2022) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17300 · Cited by 5
Fasting and cancer: from yeast to mammals
Tano, M. D., & Longo, V. D. (2022) · International review of cytology · doi:10.1016/bs.ircmb.2022.02.005 · Cited by 6
Percik, R., Oedegaard, C., Leibovici, A., & Shai, A. (2023) · Biologics · doi:10.2147/btt.s395817 · Cited by 5
Knockdown of PIK3R6 impedes the onset and advancement of clear cell renal cell carcinoma
Yang, J., Zhong, X., Gao, X., Xie, W., Chen, Y., Liao, Y., & Zhang, P. (2024) · Cell Adhesion & Migration · doi:10.1080/19336918.2024.2353920 · Cited by 5
“Targeting Class-I PI3Ks, including the PI3Kγ isoform, is crucial in cancer therapy, but their complete inhibition can lead to liver damage, hyperglycemia, and insulinemia, which paradoxically activates PI3K in tumors and reduces the effectiveness of pan-PI3K inhibitors [20,21].”
BackgroundWhat is Evidence-Based Functional Medicine in the 21st Century?
Bland, J. S. (2019) · PubMed Central · Cited by 5
The critical need for guidance in managing glycaemic control in patients with cancer
Giovannucci, E. L. (2021) · Diabetic Medicine · doi:10.1111/dme.14624 · Cited by 5
Dietary restriction in senolysis and prevention and treatment of disease
Aminzadeh-Gohari, S., Kofler, B., & Herzog, C. M. S. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2153355 · Cited by 5
“DR lowers the secretion of both insulin and IGF-1 by limiting glucose intake and restraining the glucose metabolism (Urbain et al. 2017; Newman et al. 2017; Hopkins et al. 2018; Stubbs et al. 2018).”
A sweet way to regulate cellular growth: OGT and mTOR join forces
Latorre‐Muro, P., & Puigserver, P. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.07.016 · Cited by 5
Insulin Reduces the Efficacy of Vemurafenib and Trametinib in Melanoma Cells
Osrodek, M., Rozanski, M., & Czyż, M. (2020) · Cancer Management and Research · doi:10.2147/cmar.s263767 · Cited by 5
Caloric restriction alters lipid metabolism to contribute to tumor growth inhibitionPreprint
Lien, E. C., Westermark, A. M., Li, Z., Sapp, K. M., & Heiden, M. G. V. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.09.984302 · Cited by 5
A landscape of synergistic drug combinations in non-small-cell lung cancerPreprint
Nair, N. U., Greninger, P., Friedman, A. A., Amzallag, A., Cortez, E., Sahu, A. D., Lee, J. S., Dastur, A., Egan, R. K., Murchie, E., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.06.03.447011 · Cited by 5
Hostallero, D. E., Wei, L., Wang, L., Cairns, J., & Emad, A. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.06.451273 · Cited by 5
“PI3K activation and enhanced glucose uptake [53-58] and plays a role in cytotoxic therapy 379 response [59].”
Tirzepatide inhibits tumor growth in mice with diet-induced obesityPreprint
Huang, L., Zeng, J., Wang, Y., & Pollak, M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.22.546093 · Cited by 5
Carrier-Free Cisplatin–Dactolisib Nanoparticles for Enhanced Synergistic Antitumor Efficacy
Zhang, M., Tan, Q., Gonca, S., Lan, M., Qian, B., Chen, X., & Radacsi, N. (2025) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.4c00672 · Cited by 4
Deciphering the MYCN-driven metabolic microenvironment of neuroblastoma
Wolf, A. B., Leardini, D., Li, L., Masetti, R., Lyssiotis, C. A., & Barbieri, E. (2025) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2025.08.005 · Cited by 5
“A KD can enhance the efficacy of both standard chemotherapy and targeted agents, including PI3K inhibitors, by lowering blood insulin and deactivating the insulin receptor in solid tumors [111].”
Catabolic rewiring in cancer impacts dietary interventions
Chinopoulos, C. (2025) · Communications Biology · doi:10.1038/s42003-025-09333-9 · Cited by 6
“Conversely, calorie restriction, a ketogenic or low-carbohydrate diet, cuts fasting insulin by 30 – 70% and IGF-1 by 15 – 40% 2 ; tumors that are endocrine-dependent slow their proliferation and become moresensitivetochemotherapy,radiotherapy,orPI3Kinhibition,asseenin PTEN/PIK3CA-mutantendometrialcancer 370 .”
Overcoming Therapeutic Resistance in Triple-Negative Breast Cancer: Targeting the Undrugged Kinome
Lee, C. H., Nguyen, T. M., Lee, Y., Choi, S. G., Nguyễn, P. N., Park, J. H., & Park, M. K. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms27010450 · Cited by 8
“Furthermore, pathway reactivation triggered by PI3K inhibition—through insulin feedback loops [79] or the release of mTORC1-S6K1 inhibition [80]—remains a major factor limiting the efficacy of monotherapies.”
Secondary causes of diabetes: a crossroad of endocrinology and oncology
Hee, N. K. Y., Lim, Q. H., Khunti, K., Ooi, Y., Yen, I., Saad, M. B., Ekinci, E. I., Li, H., Vethakkan, S. R., Chan, J. C. N., et al. (2026) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(26)00027-6 · Cited by 4
Kim, Y. K., KAMEO, Y., Tanaka, S., & ADACHI, T. (2024) · JBMR Plus · doi:10.1093/jbmrpl/ziad003 · Cited by 4
Kareva, I. (2024) · Aging and Cancer · doi:10.1002/aac2.12073 · Cited by 5
“Finally, we build upon the observations of Hopkins et al. 10 , where the authors showed that development of diabetic phenotype in mouse cancer models resulted in emergence of reversible therapeutic resistance to PI3K inhibitors due to growth signals from elevated insulin overwhelming the cytotoxic…”
BackgroundInfluential
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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