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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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“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
“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 158
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 168
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
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 144
“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 131
“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 140
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 138
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
“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 139
“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 129
“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 128
“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 127
“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
Cao, M., Isaac, R., Yan, W., Ruan, X., Jiang, L., Wan, Y., Wang, J., Wang, E., Caron, C., Neben, S., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00919-7 · Cited by 121
“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
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 119
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
“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 123
“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
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 132
“recommendations, and improve the understanding of how diet modulates the efficacy of drugs and treatments (133).”
BackgroundWright, S. C. E., Vasilevski, N., Serra, V., Rodon, J. A., & Eichhorn, P. J. A. (2021) · Cancers · doi:10.3390/cancers13071538 · Cited by 116
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 138
Hoong, C. W. S., & Chua, M. W. J. (2021) · Endocrinology · doi:10.1210/endocr/bqab079 · Cited by 112
Kondo, H., Ratcliffe, C. D. H., Hooper, S., Ellis, J., MacRae, J. I., Hennequart, M., Dunsby, C. W., Anderson, K. I., & Sahai, E. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108750 · Cited by 109
“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
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 108
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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