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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PI3K inhibitors suppress glucose uptake by muscle and other tissues, causing elevated blood glucose and pancreatic insulin release; the insulin surge reactivates PI3K signaling in the tumor and limits the efficacy of PI3K inhibitors on tumor growth.
“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]
A low-carbohydrate, ketogenic diet blunts the hyperglycemia and insulin release that accompany PI3K inhibition and improves the efficacy of PI3K inhibitors on tumor growth in mice.
“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]
The direct use of specific diets, or the modulation of inter‐organ communication, could have a pharmacological effect on its own or increase the efficiency of pharmacological approaches.
“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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“This research area stems from pioneering work showing that the systemic hyperinsulinemia observed in cancer patients treated with a PI3K inhibitor, which is able to reactivate mTOR signaling in cancer cells, can be blocked by a ketogenic diet, allowing more effective control of tumor growth than PI3K inhibitor treatme…”
BackgroundMetabolic pathways in obesity-related breast cancer
Brown, K. A. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00487-0 · Cited by 235 · see citing works
Targeting mTOR and Metabolism in Cancer: Lessons and Innovations
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“An intriguing concept is the integration of dietary manipulation with targeted therapies to improve patient response [330].”
BackgroundThe present and future of PI3K inhibitors for cancer therapy
Castel, P., Toska, E., Engelman, J. A., & Scaltriti, M. (2021) · Nature Cancer · doi:10.1038/s43018-021-00218-4 · Cited by 222 · see citing works
Molecular hybridization: a powerful tool for multitarget drug discovery
Pinheiro, P. D. S. M., Franco, L. S., Montagnoli, T. L., & Fraga, C. A. M. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2322990 · Cited by 224 · see citing works
Novel roles of phosphoinositides in signaling, lipid transport, and disease
Hammond, G. R. V., & Burke, J. E. (2020) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.12.007 · Cited by 203 · see citing works
“Suppressing this insulin feedback through either dietary or pharmacological approaches shows promise for increased efficacy of PI3K inhibitors as cancer therapeutics [74].”
BackgroundInsulin action at a molecular level – 100 years of progress
White, M. F., & Kahn, C. R. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101304 · Cited by 214 · see citing works
“adipocyte differentiationdconfirming that the PI3K is a critical node in insulin’s action [32,33].”
BackgroundRadiotherapy as a tool to elicit clinically actionable signalling pathways in cancer
Petroni, G., Cantley, L. C., Santambrogio, L., Formenti, S. C., & Galluzzi, L. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00579-w · Cited by 215 · see citing works
Self-citationStem Cell Plasticity and Dormancy in the Development of Cancer Therapy Resistance
Angelis, M. L. D., Francescangeli, F., Torre, F. L., & Zeuner, A. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00626 · Cited by 203 · see citing works
“A link between diet-related factors and therapy has recently emerged by studies showing that a hypoglycemic diet improves the effectiveness of PI3K inhibitors (181).”
BackgroundEffects of dietary intervention on human diseases: molecular mechanisms and therapeutic potential
Xiao, Y.-L., Gong, Y., Qi, Y.-J., Shao, Z., & Jiang, Y.-Z. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01771-x · Cited by 212 · see citing works
“268 Finally, the combination of serine deprivation and biguanide treatment, such as phenformin and metformin, can lead to metabolic stress in cancer cells.”
BackgroundLima, J. E. B. F., Moreira, N. C. S., & Sakamoto-Hojo, E. T. (2022) · Mutation Research/Genetic Toxicology and Environmental Mutagenesis · doi:10.1016/j.mrgentox.2021.503437 · Cited by 203 · see citing works
Dietary Approaches to Cancer Therapy
Tajan, M., & Vousden, K. H. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.04.005 · Cited by 208 · see citing works
PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment
Leiphrakpam, P., & Are, C. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063178 · Cited by 193 · see citing works
“Further investigation in clinical trials is required to determine the full potential of dual TORC1/2 inhibitors in CRC treatment.”
BackgroundLysosome: The metabolic signaling hub
Lamming, D. W., & Bar‐Peled, L. (2018) · Traffic · doi:10.1111/tra.12617 · Cited by 183 · see citing works
PTEN-opathies: from biological insights to evidence-based precision medicine
Yehia, L., Ngeow, J. Y. Y., & Eng, C. (2019) · Journal of Clinical Investigation · doi:10.1172/jci121277 · Cited by 178 · see citing works
“Moreover, PI3K inhibition can result in therapeutic resistance in PIK3CA-mutant cell lines due to a rebound insulin-dependent feedback mechanism (140), or failure to suppress CDK4/6 as evidenced through persistent RB phosphorylation (143).”
BackgroundInter‐organ communication: a gatekeeper for metabolic health
Castillo‐Armengol, J., Fajas, L., & Lopez‐Mejia, I. C. (2019) · The EMBO Reports · doi:10.15252/embr.201947903 · Cited by 178 · see citing works
“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 ].”
Beyond genetics: driving cancer with the tumour microenvironment behind the wheel
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Wen, P. Y., Touat, M., Alexander, B. M., Mellinghoff, I. K., Ramkissoon, S. H., McCluskey, C. S., Pelton, K., Haidar, S., Basu, S. S., Gaffey, S. C., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.18.01207 · Cited by 171 · see citing works
“Median age, years (range) 55 (39-68) 56 (29-80)”
Vasan, N., & Cantley, L. C. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00633-1 · Cited by 169 · see citing works
Self-citationOverview of the relevance of PI3K pathway in HR-positive breast cancer
Vasan, N., Toska, E., & Scaltriti, M. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz281 · Cited by 166 · see citing works
“In a recent report, mouse models of multiple cancers including ERþ BC showed increased blood glucose and insulin on treatment with a wide range of small molecule inhibitors of the PI3K pathway, including PI3Ka-specific inhibitors [35].”
BackgroundBeyond PI3Ks: targeting phosphoinositide kinases in disease
Burke, J. E., Triscott, J., Emerling, B. M., & Hammond, G. R. V. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00582-5 · Cited by 156 · see citing works
LeBoeuf, S. E., Wu, W. L., Karakousi, T. R., Karadal, B., Jackson, S. R., Davidson, S. M., Wong, K.-K., Koralov, S. B., Sayin, V. I., & Papagiannakopoulos, T. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.012 · Cited by 150 · see citing works
“Our work, as well as that of others, support that metabolite restriction through pharmacological or dietary means can effectively suppress tumor growth (Elia et al., 2017; Gao et al., 2019; Gwinn et al., 2018; Hopkins et al., 2018; Knott et al., 2018; Loayza-Puch et al., 2016; Maddocks et al., 2013; Maddocks et al., 2…”
BackgroundFasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape
Salvadori, G., Zanardi, F., Iannelli, F., Lobefaro, R., Vernieri, C., & Longo, V. D. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.10.008 · Cited by 159 · see citing works
“Notably, high glucose levels could also promote high insulin levels, well known to promote cancer growth (Hopkins et al., 2018).”
BackgroundThe Opposing Roles of PIK3R1/p85α and PIK3R2/p85β in Cancer
Vallejo-Díaz, J., Chagoyen, M., Olazabal-Morán, M., González-Garcı́a, A., & Carrera, A. C. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.02.009 · Cited by 159 · see citing works
Developing dietary interventions as therapy for cancer
Taylor, S. R., Falcone, J. N., Cantley, L. C., & Goncalves, M. D. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00485-y · Cited by 160 · see citing works
Self-citationA framework for examining how diet impacts tumour metabolism
Lien, E. C., & Vander Heiden, M. G. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0198-5 · Cited by 139 · see citing works
Metabolic Fingerprinting Links Oncogenic PIK3CA with Enhanced Arachidonic Acid-Derived Eicosanoids
Koundouros, N., Karali, E., Tripp, A., Valle, A., Inglese, P., Perry, N. J. S., Magee, D. J., Virmouni, S. A., Elder, G. A., Tyson, A. L., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.053 · Cited by 141 · see citing works
“Recent evidence suggests that oneway to enhance their efficacy is by suppressing their insulin feedback through adoption of a ketogenic diet (Hopkins et al., 2018).”
BackgroundGoulden, B. D., Pacheco, J. E., Dull, A., Zewe, J. P., Deiters, A., & Hammond, G. R. V. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201809026 · Cited by 139 · see citing works
“PI(3,4)P2 has instead been viewed as either a degradation product (Ishihara et al., 1999) or an alternative activator of the pathway (Ebner et al., 2017).”
BackgroundThe strange case of AMPK and cancer: Dr Jekyll or Mr Hyde?
Vara‐Ciruelos, D., Russell, F. M., & Hardie, D. G. (2019) · Open Biology · doi:10.1098/rsob.190099 · Cited by 136 · see citing works
Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment
Peck, B., & Schulze, A. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.09.007 · Cited by 135 · see citing works
The Ketogenic Diet: Evidence for Optimism but High-Quality Research Needed
Ludwig, D. S. (2020) · The Journal of Nutrition · doi:10.1093/jn/nxz308 · Cited by 133 · see citing works
“However, this diet might act synergistically with other treatments, such as phosphoinositide 3-kinase inhibitors (43), and aid prevention, possibilities that warrant investigation.”
BackgroundIs it still worth pursuing the repurposing of metformin as a cancer therapeutic?
Lord, S., & Harris, A. L. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02204-2 · Cited by 132 · see citing works
“Activation of the insulin receptor promotes downstream PI3K-AKTmtor signalling and growth in tumour models [15] and increased insulin levels are associated with higher cancer incidence and mortality [16].”
BackgroundRedox Regulation in Cancer Cells during Metastasis
Tasdogan, A., Ubellacker, J. M., & Morrison, S. J. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0558 · Cited by 123 · see citing works
“Ketogenic diets are designed to minimize dietary carbohydrates, reducing blood glucose and insulin levels (159).”
BackgroundKetogenic Diet in Cancer Prevention and Therapy: Molecular Targets and Therapeutic Opportunities
Talib, W. H., Mahmod, A. I., Kamal, A., Rashid, H. M., Alashqar, A. M. D., Khater, S. H., Jamal, D., & Waly, M. I. (2021) · Current Issues in Molecular Biology · doi:10.3390/cimb43020042 · Cited by 124 · see citing works
“Moreover, the PI3K is genetically mutated or overexpressed in a wide variety of cancers, and results in drug resistance, which indicates that the KD keeping blood sugar levels low would improve the ability of PI3K inhibitors to treat cancer [27].”
BackgroundInfluentialGlucose Metabolism in Pancreatic Cancer
Liang, Y., Raj, P. S., Yao, W., & Ying, H. (2019) · Cancers · doi:10.3390/cancers11101460 · Cited by 122 · see citing works
“Treating PDAC xenograft models with canagliflozin, a SGLT2 inhibitor used for type 2 diabetes, not only inhibited tumor growth but also sensitized tumors to PI3K inhibitor [19,20].”
Current State and Future Challenges for PI3K Inhibitors in Cancer Therapy
Sirico, M., D’Angelo, A., Gianni, C., Casadei, C., Merloni, F., & De Giorgi, U. (2023) · Cancers · doi:10.3390/cancers15030703 · Cited by 121 · see citing works
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“PI3K inhibitor treatment induces hyperinsulinemia, which compromises treatment effectiveness by reactivating the PI3K pathway in tumours 53 .”
Ferrer, M., Mourikis, N., Davidson, E. E., Kleeman, S. O., Zaccaria, M., Habel, J., Rubino, R., Gao, Q., Flint, T. R., Young, L., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.05.008 · Cited by 121 · see citing works
Self-citationKetogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth
Yang, L., TeSlaa, T. A., Ng, S., Nofal, M., Wang, L., Lan, T., Zeng, X., Cowan, A. J., McBride, M. J., Lu, W., et al. (2022) · Med · doi:10.1016/j.medj.2021.12.008 · Cited by 117 · see citing works
SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia
Nasiri, A. R., Rodrigues, M. R. D. S., Li, Z., Leitner, B. P., & Perry, R. J. (2019) · Cancer & Metabolism · doi:10.1186/s40170-019-0203-1 · Cited by 116 · see citing works
“Interfering with insulin signaling may slow tumor growth [21], while activation of the insulin receptor may promote tumor progression [22, 23] in murine models, although there have also been publications demonstrating the absence of an effect of insulin on tumor growth [24].”
BackgroundNutrient metabolism and cancer in the in vivo context: a metabolic game of give and take
Altea‐Manzano, P., Cuadros, A. M., Broadfield, L. A., & Fendt, S. (2020) · EMBO Reports · doi:10.15252/embr.202050635 · Cited by 119 · see citing works
“For instance, taking advantage of the insulin-sensitizing effects of the ketogenic diets, response to PI3K inhibitors (which is dampened in the presence of high insulin levels) can be improved in multiple tumor types with varied mutational profiles in mice (Hopkins et al , 2018).”
InfluentialPI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment
Collins, N. B., Abosy, R. A., Miller, B. C., Bi, K., Zhao, Q., Quigley, M. M., Ishizuka, J. J., Yates, K. B., Pope, H. W., Manguso, R. T., et al. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-003402 · Cited by 114 · see citing works
Research gaps and opportunities in precision nutrition: an NIH workshop report
Lee, B. Y., Ordovás, J. M., Parks, E. J., Anderson, C. A. M., Barabási, A.-Ĺ., Clinton, S. K., de la Haye, K., Duffy, V. B., Franks, P. W., Ginexi, E. M., et al. (2022) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqac237 · Cited by 122 · see citing works
“recommendations, and improve the understanding of how diet modulates the efficacy of drugs and treatments (133).”
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Metabolic interplays between the tumour and the host shape the tumour macroenvironment
Altea‐Manzano, P., Decker-Farrell, A. R., Janowitz, T., & Erez, A. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-024-00786-4 · Cited by 127 · see citing works
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“possibility being that a subset of cells persist under PI3K pathway inhibition by regulating glycolysis through other mechanisms (Hopkins et al., 2018; Liu et al., 2011).”
BackgroundMolinaro, A., Becattini, B., Mazzoli, A., Bleve, A., Radici, L., Maxvall, I., Sopasakis, V. R., Molinaro, A., Bäckhed, F., & Solinas, G. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.03.010 · Cited by 108 · see citing works
Targeting PI3K signaling in cancer: Challenges and advances
Santis, M. C. D., Gulluni, F., Campa, C. C., Martini, M., & Hirsch, E. (2019) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2019.03.003 · Cited by 105 · see citing works
- 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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