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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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“As examples, cancer cell sensitivity to treatment with methotrexate or phosphotidylinositol-3 kinase inhibitors is enhanced by dietary interventions that increase histidine metabolism (80) or reduce hyperglyemia-induced insulin sectretion (81), respectively.”
BackgroundRoskoski, R. J. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105579 · Cited by 62
“Data suggest that insulin feedback induced by PI 3-kinase inhibitors reactivate the PI3K-mTOR signaling axis in tumors, thereby compromising their effectiveness [127].”
BackgroundPTEN in Hereditary and Sporadic CancerPreprint
Ngeow, J. Y. Y., & Eng, C. (2019) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a036087 · Cited by 61
“Moreover, PI3K inhibition can result in therapeutic resistance in PIK3CA mutant cell lines as a result of a rebound insulin-dependent feedback mechanism (Hopkins et al. 2018) or failure to suppress CDK 4/6 as evidenced through persistent RB phosphorylation (Vora et al.”
BackgroundTherapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy
Ye, J., Wu, J., & Liu, B. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188866 · Cited by 63
Voß, M., Wenger, K. J., von Mettenheim, N., Bojunga, J., Vetter, M., Diehl, B., Franz, K., Gerlach, R., Ronellenfitsch, M. W., Harter, P. N., et al. (2021) · European Journal of Nutrition · doi:10.1007/s00394-021-02666-1 · Cited by 57
Amino acid variability, tradeoffs and optimality in human diet
Dai, Z., Zheng, W., & Locasale, J. W. (2022) · Nature Communications · doi:10.1038/s41467-022-34486-0 · Cited by 61
Rizzieri, D., Paul, B. A., & Kang, Y. (2019) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2019.05 · Cited by 61
“Ultimately, glycolysis, the TCA cycle, gluconeogenesis, fatty acid metabolism, and protein synthesis are all interconnected and exist in a highly regulated and interdependent environment designed to maintain homeostasis[31-33].”
BackgroundTang, X., Li, G., Shi, L., Su, F., Qian, M., Liu, Z., Meng, Y., Sun, S., Li, J., & Liu, B. (2021) · Nature Communications · doi:10.1038/s41467-021-25274-3 · Cited by 62
Middleton, G., Robbins, H. L., André, F., & Swanton, C. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.11.004 · Cited by 59
A landscape of response to drug combinations in non-small cell lung cancer
Nair, N. U., Greninger, P., Zhang, X., Friedman, A. A., Amzallag, A., Cortez, E., Sahu, A. D., Lee, J. S., Dastur, A., Egan, R. K., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39528-9 · Cited by 63
“Indeed, the insulin receptor family is a potent and major (even likely the ancestral) activator of PI3K amongst RTKs 45,46 .”
BackgroundTargeting obesity-related dysfunction in hormonally driven cancers
Rubinstein, M. M. Z., Brown, K. A., & Iyengar, N. M. (2021) · British Journal of Cancer · doi:10.1038/s41416-021-01393-y · Cited by 61
Ketogenic Diet for Cancer: Critical Assessment and Research Recommendations
Lane, J., Brown, N. I., Williams, S., Plaisance, E. P., & Fontaine, K. R. (2021) · Nutrients · doi:10.3390/nu13103562 · Cited by 57
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Liu, Y., Sun, Y., Yang, J., Wu, D., Yu, S., Liu, J., Hu, T., Luo, J., & Zhou, H. (2024) · Molecular Cancer · doi:10.1186/s12943-024-01993-1 · Cited by 59
“Moreover, tumor-bearing mice in which DNMT1 was targeted As evidenced in prior research, the transient hyperglycemia caused by PI3K inhibition often remains within a few hours, as insulin feedback mechanisms kick in to restore normal glucose homeostasis [54].”
BackgroundSelf-citationShi, Z., Wulfkuhle, J. D., Nowicka, M., Gallagher, R. I., Saura, C., Nuciforo, P. G., Calvo, I., Andersen, J., Passos‐Coelho, J. L., Gil‐Gil, M., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2498 · Cited by 55
Metabolic regulation of T cells in the tumor microenvironment by nutrient availability and diet
Zhao, S., Peralta, R. M., Avina-Ochoa, N., Delgoffe, G. M., & Kaech, S. M. (2021) · Seminars in Immunology · doi:10.1016/j.smim.2021.101485 · Cited by 58
Tankova, T. I., Senkus, E., Beloyartseva, M., Borštnar, S., Catrinoiu, D., Фролова, М. А., Hegmane, A., Janež, A., Krnić, M., Lengyel, Z., et al. (2022) · Cancers · doi:10.3390/cancers14071598 · Cited by 60
“The hyperinsulinemia that occurs in patients with alpelisib-induced hyperglycemia may provide breast cancer cells with a survival mechanism and reduce the efficacy of alpelisib as demonstrated in preclinical studies [6,23,25,28,29].”
BackgroundInfluentialCyclic fasting-mimicking diet in cancer treatment: Preclinical and clinical evidence
Vernieri, C., Ligorio, F., Tripathy, D., & Longo, V. D. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.06.014 · Cited by 57
Obesity and the Impact on Cutaneous Melanoma: Friend or Foe?
Smith, L. K., Arabi, S., Lelliott, E. J., McArthur, G. A., & Sheppard, K. E. (2020) · Cancers · doi:10.3390/cancers12061583 · Cited by 59
“Interestingly, efficacy of PI3K inhibitors appears to be limited due to systemic glucose-insulin feedback caused by targeted inhibition of the PI3K pathway, that is sufficient to reactivate PI3K signalling in tumor cells across multiple tumor models in mice [116].”
BackgroundMetabolite releasing polymers control dendritic cell function by modulating their energy metabolism
Mangal, J. L., Inamdar, S., Yang, Y., Dutta, S., Wankhede, M., Shi, X., Gu, H., Green, M., Rege, K., Curtis, M., et al. (2020) · Journal of Materials Chemistry B · doi:10.1039/d0tb00790k · Cited by 50
Browne, I. M., & Okines, A. F. C. (2024) · Cancers · doi:10.3390/cancers16122259 · Cited by 53
“Yang et al. demonstrated that ER also drives PI3K/AKT activation in response to mTORC1 inhibition with everolimus [82].”
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“, PI3KCA or AKT), or, finally, loss-of-function or reduced levels of PTEN, LKB1, or inositol polyphosphate 4-phosphatase type II (INPP4B) tumor suppressor proteins [24, 25].”
BackgroundThe effect of a ketogenic diet and synergy with rapamycin in a mouse model of breast cancer
Zou, Y., Fineberg, S., Pearlman, A. W., Feinman, R. D., & Fine, E. J. (2020) · PLoS ONE · doi:10.1371/journal.pone.0233662 · Cited by 49
Immunometabolism in the Tumor Microenvironment
Roy, D. G., Kaymak, I., Williams, K. S., Ma, E. H., & Jones, R. G. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055817 · Cited by 49
PI3K inhibition in breast cancer: Identifying and overcoming different flavors of resistance
Vitale, S. R., Martorana, F., Stella, S., Motta, G., Inzerilli, N., Massimino, M., Tirrò, E., Manzella, L., & Vigneri, P. G. (2021) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2021.103334 · Cited by 47
Bruton’s Tyrosine Kinase and Its Isoforms in Cancer
Wang, X., Kokabee, L., Kokabee, M., & Conklin, D. S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.668996 · Cited by 48
Liu, D., Weintraub, M. A., Garcia, C., Goncalves, M. D., Sisk, A. E., Casas, A., Harding, J. J., Harnicar, S. J., Drilon, A. E. D. C., Jhaveri, K. L., et al. (2022) · Cancer Medicine · doi:10.1002/cam4.4579 · Cited by 47
Self-citationZhou, R. W., Xu, J., Martin, T. C., Zachem, A. L., He, C., Ozturk, S., Demircioğlu, D., Bansal, A., Trotta, A. P., Giotti, B., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33377-8 · Cited by 49
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“For example, inhibition of insulin-activated phosphoinositide-3-kinase (PI3K) has been associated with adverse systemic effects in patients, depending on the degree of insulin resistance in pancreatic tumor patients (11).”
BackgroundInfluentialPI3K pathway in prostate cancer: All resistant roads lead to PI3K
Park, S., Kim, Y. S., Kim, D. Y., So, I., & Jeon, J. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.09.001 · Cited by 45
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“PI3K is known to play vital roles in the regulation of biological functions of tumor cells, such as cell survival, cell growth, and migration [1, 2].”
Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back
Schmidt, V., Hogan, A. E., Fallon, P. G., & Schwartz, C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.932893 · Cited by 51
“Signaling of mTORC1 is enhanced by insulin and influences Th1, Th2 and Th17 cell differentiation (44, 55).”
BackgroundPI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma
Duchatel, R. J., Jackson, E. R., Parackal, S., Kiltschewskij, D. J., Findlay, I. J., Mannan, A., Staudt, D. E., Thomas, B. C., Germon, Z. P., Laternser, S., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci170329 · Cited by 45
“Indeed, insulin feedback is a well characterized mechanism of resistance to PI3K inhibitors in vivo (22), an important systemic consideration when testing paxalisib against DIPG in vivo.”
Cancer Treatment With the Ketogenic Diet: A Systematic Review and Meta-analysis of Animal Studies
Li, J., Zhang, H., & Dai, Z. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.594408 · Cited by 45
“Furthermore, KD has been reported to enhance the efficacy of targeted therapy and overcome drug resistance in several tumor models when using PI3K inhibitors (11), as well as reduce metastatic potential (12, 13).”
BackgroundPhosphoinositide 3-Kinase (PI3K) Inhibitors and Breast Cancer: An Overview of Current Achievements
Bertucci, A., Bertucci, F., & Gonçalvès, A. (2023) · Cancers · doi:10.3390/cancers15051416 · Cited by 45
“Importantly, such hyperglycemia might induce plasma insulin rebound, thus leading to restoration of PI3K signaling and, ultimately, to treatment resistance [146].”
BackgroundZhang, Z., & Richmond, A. J. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.648663 · Cited by 44
Recent advances in drug delivery and targeting for the treatment of pancreatic cancer
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Dietary and metabolic effects on intestinal stem cells in health and disease
Shay, J. E. S., & Yilmaz, Ö. H. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00980-7 · Cited by 47
“In a mouse model of acute myeloid leukaemia, a ketogenic diet was found to accelerate disease progression and was associated with reduced survival 172 .”
Nixon, M. J., Formisano, L., Mayer, I. A., Estrada, M. V., Ericsson, P. I. G., Isakoff, S. J., Forero, A., Won, H. H., Sanders, M. E., Solit, D. B., et al. (2019) · npj Breast Cancer · doi:10.1038/s41523-019-0126-6 · Cited by 42
Self-citation
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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