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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, it has been suggested that the subsequent suppression of the insulin feedback could enhance the efficacy of PI3K inhibitors, with possible beneficial effect on the acute myeloid leukemia treatment [99].”
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“Inhibition of PI3K leads to acute insulin resistance, blocking glucose uptake in skeletal muscle and adipose tissue, activating hepatic glycogenolysis, causing hyperglycemia and a compensatory increase in circulating insulin 1,26,27 .”
Self-citationLow-Carbohydrate High-Fat Diet: A SWOC Analysis
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“Finally, these experimental results as well as the most recent work on PI3Ka inhibitors (17, 18) are used to refine the network-based mathematical model and incorporate the observed cell line–specific effects into a new version (the 2020 version) of the model (Fig.”
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“Hyperinsulinemia may be targeted by diet alterations (68) or via re-positioning diabetes drugs such as the insulinsensitizing drug metformin as adjuvant ADT therapy, to reduce circulating ligand levels (70) (Figure 8).”
Ketogenic diet and cancer: Fad or fabulous?
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“Another resistance mechanism is the suppression of the insulin feedback loop, whereby systemic hyperglycemia and hyperinsulinemia induced by PI3K inhibition can reactivate the PAM pathway in cancer cells 52 .”
BackgroundMetformin: From diabetes to cancer to prolongation of life
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“When treated with insulin lowering methods, including SGLT-2 inhibitor and the ketogenic diet, the tumor cells had a better response to PI3K inhibitors (Hopkins et al., 2018).”
BackgroundMethodFuture of ChatGPT in Pharmacovigilance
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“Despite the issues with one of the citations, the other source provided by Chat-GPT did accurately discuss the mechanism of PI3K inhibition, which blocks insulin signaling and glucose uptake [10].”
BackgroundRole of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic
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“However, it was notable in this study that SGLT-2 inhibition led to a greater restoration of PI3K-inhibitor sensitivity than metformin [168].”
BackgroundA multidisciplinary approach to optimizing care of patients treated with alpelisib
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“In animal models of cancer, adding SGLT2i to a PI3Ki improved hyperglycemia and slowed tumor growth [46].”
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“For instance, Hopkins and colleagues observed that a KD rendered PI3K inhibitors, which are normally inactive against PDAC, effective in a KPC cell line–based orthotopic allograft tumors (14).”
BackgroundKetogenic diets composed of long-chain and medium-chain fatty acids induce cardiac fibrosis in mice
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“PTEN loss results in increased activation of PI3K (Stambolic et al , 1998; Haddadi et al , 2018) and addiction to PI3K pathway activity (Chen et al , 2006; Jia et al , 2008; Wee et al , 2008; Vasudevan et al , 2009; Sangai et al , 2012; Hancox et al , 2015) in the affected cells.”
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“enhanced tumor growth and compromised treatment effectiveness in mouse models (14, 15).”
BackgroundGanitumab and metformin plus standard neoadjuvant therapy in stage 2/3 breast cancer
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“Furthermore, constitutive high blood glucose and insulin levels facilitate tumor growth through an insulin/ PI3K/mTOR feedback loop, which may also compromise the treatment effectiveness of PI3K inhibitors (1, 33).”
Diet and Exercise in Cancer Metabolism
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“org glucose reabsorption in the kidney and presumably decreases glycolytic rate in the tumor through reducing insulin signaling (39).”
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“10 Given the complexity of anti ‐ hyperglycemic treatment considerations in this setting, multidisciplinary support including consultation with dieticians and endocrinologists is warranted.”
BackgroundMolecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers
Shan, K. S., Bonano-Rios, A. M., Theik, N. W. Y., Hussein, A. M., & Blaya, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25041973 · Cited by 31
“IRS-1 stimulation increases GLUT-1 receptor expression and downregulates GLUT4 membrane translocation [248–251].”
BackgroundAdvances in Diet and Physical Activity in Breast Cancer Prevention and Treatment
Khalifa, A., Guijarro, A. I., & Nencioni, A. (2024) · Nutrients · doi:10.3390/nu16142262 · Cited by 37
“Finally, studies show that KDs help avoid high blood glucose and insulin levels in response to treatment with PI3K, AKT or mTOR inhibitor (the so-called insulin-feedback) and cooperate with these agents in achieving optimal tumor growth control [89].”
BackgroundResultBorsari, C., Keleş, E., Rageot, D., Treyer, A., Bohnacker, T., Bissegger, L., Pascale, M. D., Melone, A., Sriramaratnam, R., Beaufils, F., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00620 · Cited by 28
Ketogenic diets slow melanoma growth in vivo regardless of tumor genetics and metabolic plasticity
Weber, D. D., Aminzadeh-Gohari, S., Thapa, M., Redtenbacher, A.-S., Catalano, L., Capelôa, T., Vazeille, T., Emberger, M., Felder, T. K., Feichtinger, R. G., et al. (2022) · Cancer & Metabolism · doi:10.1186/s40170-022-00288-7 · Cited by 29
“For instance, low-carbohydrate/ high-fat ketogenic diets (KDs) have been proposed to target altered glucose metabolism in cancers by reducing the levels of circulating glucose and insulin and insulinlike growth factor-1 to perturb activation of oncogenic signaling cascades downstream of the insulin receptor [2, 3].”
BackgroundBuga, A., Harper, D. G., Sapper, T. N., Hyde, P. N., Fell, B., Dickerson, R. M., Stoner, J. T., Kackley, M. L., Crabtree, C. D., Decker, D. D., et al. (2024) · PLoS ONE · doi:10.1371/journal.pone.0296523 · Cited by 26
“…mitochondrial hormesis, restoring normal oxidative phosphorylation, influencing epigenetic modulation, reducing ’cancer-related upregulation of phosphoinositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling, and lessening hyperglycemia induced by cancer medication [14–18].”
Rogava, M., Aprati, T. J., Chi, W.-Y., Melms, J. C., Hug, C. B., Davis, S. H., Earlie, E. M., Chung, C., Deshmukh, S. K., Wu, S. K., et al. (2024) · Nature Cancer · doi:10.1038/s43018-023-00704-x · Cited by 27
“Recent studies demonstrate that hyperinsulinemia, either in the context of insulin resistance or in response to systemic PI3K inhibition, increases tumor growth of subcutaneously implanted patient-derived xenograft models through inhibition of host PI3K 28,38,39 .”
BackgroundResultInfluentialSelf-citationTargeting PI3K inhibitor resistance in breast cancer with metabolic drugs
Gremke, N., Besong, I., Stroh, A., von Wichert, L., Witt, M., Elmshäuser, S., Wanzel, M., Fromm, M. F., Taudte, R. V., Schmatloch, S., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02180-4 · Cited by 31
“77 80 – 82 Despite correlating signi fi cantly in HR + /Her2 − and TNBC, no association of p4E-BP1 T37/46 and p62 was observed in Her2 + BC patients (Fig.”
McPhail, J. A., & Burke, J. E. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-50621-6_9 · Cited by 26
Rodrigues, D. A., Pinheiro, P. D. S. M., & Fraga, C. A. M. (2020) · ChemMedChem · doi:10.1002/cmdc.202000643 · Cited by 28
Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma
Nomura, M., Ohuchi, M., Sakamoto, Y., Kudo, K., Yaku, K., Soga, T., Sugiura, Y., Morita, M., Hayashi, K., Miyahara, S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-43630-3 · Cited by 29
Signaling pathway dysregulation in breast cancer
Ryspayeva, D., Seyhan, A. A., MacDonald, W., Purcell, C., Roady, T. J., Ghandali, M., Verovkina, N., El‐Deiry, W. S., Taylor, M. S., & Graff, S. L. (2025) · Oncotarget · doi:10.18632/oncotarget.28701 · Cited by 31
Chen, X., Ariss, M., Ramakrishnan, G., Nogueira, V., Blaha, C. S., Putzbach, W., Islam, A. B. M. M. K., Frolov, M. V., & Hay, N. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.08.017 · Cited by 26
Ketogenic Diets and their Therapeutic Potential on Breast Cancer: A Systemic Review
Jemal, M., Shibabaw, T., & Dejenie, T. A. (2021) · Cancer Management and Research · doi:10.2147/cmar.s339970 · Cited by 26
“cancer, as well as acute myeloid leukemia, showed that KD improves the effectiveness of targeted therapy, particularly inhibitors of PI3K, and overcomes drug resistance.(26) This suggests that KD could be part of”
BackgroundPrecision Targeting of Mutant PI3Kα in Cancer by Selective Degradation
Vanhaesebroeck, B., Burke, J. E., & Madsen, R. R. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1411 · Cited by 26
Zapevalova, M. V., Shchegravina, E. S., Fonareva, I. P., Salnikova, D. I., Sorokin, D. V., Scherbakov, A. M., Maleev, A. A., Ignatov, S. K., Grishin, I. D., Kuimov, A. N., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810854 · Cited by 29
“Breakage of the insulin feedback might significantly improve the efficacy of PI3K inhibitors as anticancer remedies [53].”
BackgroundPI3K and AKT at the Interface of Signaling and Metabolism
Solinas, G., & Becattini, B. (2022) · Current topics in microbiology and immunology · doi:10.1007/978-3-031-06566-8_13 · Cited by 27
Alpelisib for PIK3CA -Mutated Advanced Breast Cancer
André, F., Mills, D., & Taran, T. (2019) · New England Journal of Medicine · doi:10.1056/nejmc1907856 · Cited by 26
PI3K signaling through a biochemical systems lens
Madsen, R. R., & Toker, A. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.105224 · Cited by 24
“Upon whole-body PI3K α inhibition, the ensuing hyperglycemia triggers a compensatory increase in pancreatic insulin secretion, which like the cell-intrinsic feedback loops (93, 113 – 116), seeks to overcome the pharmacological suppression of PI3K signaling (117).”
BackgroundCysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production
Noch, E., Palma, L., Yim, I., Bullen, N., Barnett, D., Walsh, A., Bhinder, B., Benedetti, E., Krumsiek, J., Gurvitch, J., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2317343121 · Cited by 29
“Glucose starvation strategies, from antihyperglycemic drugs to the ketogenic diet, have also been tested alone and in combination with putative synergistic regimens for cancer treatment (53, 54).”
Self-citationTumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy
Cuyàs, E., Verdura, S., Martín-Castillo, B., Alarcón, T., Lupu, R., Bosch‐Barrera, J., & Menéndez, J. A. (2020) · Cancers · doi:10.3390/cancers12071757 · Cited by 26
“, high-fat, very low-carbohydrate) diet preventing hyperglycemia and lowering insulin release has been shown to efficiently reduce the activation of insulin receptors in tumors and to restrict the re-activation of the PI3K pathway in tumor-bearing mice, thereby enhancing the therapeutic response to PI3K inhibitors [18…”
BackgroundTargeting the IGF/PI3K/mTOR pathway and AXL/YAP1/TAZ pathways in primary bone cancer
Truong, D. D., Lamhamedi-Cherradi, S.-E., & Ludwig, J. A. (2022) · Journal of bone oncology · doi:10.1016/j.jbo.2022.100419 · Cited by 27
Zuo, Q., Mogol, A. N., Liu, Y.-J., Casiano, A. S., Chien, C., Drnevich, J. M., Imir, O. B., Kulkoyluoglu‐Cotul, E., Park, N. H., Shapiro, D. J., et al. (2022) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-21-0781 · Cited by 25
First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors
Wei, X., Liu, F., Liu, J., Zhao, H., Zhang, Y., Wang, Z., Qiu, M., Xu, F., Yu, Q.-Q., Du, Y.-W., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34782-9 · Cited by 25
Self-citationA high affinity pan-PI3K binding module supports selective targeted protein degradation of PI3Kα
Jauslin, W. T., Schild, M., Schaefer, T., Borsari, C., Orbegozo, C., Bissegger, L., Zhanybekova, S., Ritz, D., Schmidt, A., Wymann, M. P., et al. (2023) · Chemical Science · doi:10.1039/d3sc04629j · Cited by 25
Cuyàs, E., Buxó, M., Iglesias, M. J. F., Verdura, S., Pernas, S., Dorca, J., Álvarez, I., Torres‐Martínez, S., Pérez-García, J. M., Batista-López, N., et al. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00193 · Cited by 25
“Given that new groundbreaking research has shown how dietary approaches such as carb-restricted ketogenic diets can prevent the systemic glucose-insulin feedback that impairs the efficacy of PI3K inhibitors (30), our current findings, together with the ability of metformin to significantly augment the circulating the…”
BackgroundIcard, P., Ollivier, L., Forgez, P., Otz, J., Alifano, M., Fournel, L., Loi, M., & Thariat, J. (2020) · Advances in Nutrition · doi:10.1093/advances/nmaa062 · Cited by 27
The mTOR pathway in Gliomas: From molecular insights to targeted therapies
Pournajaf, S., & Pourgholami, M. H. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118237 · Cited by 27
Dietary intervention as a therapeutic for cancer
Morita, M., Kudo, K., Shima, H., & Tanuma, N. (2020) · Cancer Science · doi:10.1111/cas.14777 · Cited by 25
Blow, T., Hyde, P. N., Falcone, J. N., Neinstein, A. B., Vasan, N., Chitkara, R., Hurd, M. A., Sardesai, S. D., Lustberg, M. B., Flory, J., et al. (2021) · Integrative Cancer Therapies · doi:10.1177/15347354211032283 · Cited by 23
Self-citationLiver Metastatic Breast Cancer: Epidemiology, Dietary Interventions, and Related Metabolism
Zuo, Q., Park, N. H., Lee, J. K., & Madak‐Erdogan, Z. (2022) · Nutrients · doi:10.3390/nu14122376 · Cited by 26
“Ketone bodies produced by the liver benefit normal cells but not cancer cells [99,100].”
BackgroundDietary Components, Microbial Metabolites and Human Health: Reading between the Lines
Guo, Y., Bian, X., Liu, J., Zhu, M. Q., Li, L., Yao, T., Tang, C., Ravichandran, V., Liao, P., Papadimitriou, K., et al. (2020) · Foods · doi:10.3390/foods9081045 · Cited by 23
“Moreover, the Ketogenic diet can improve the efficacy of PI3K inhibitors by inhibiting the disorder of glucose–insulin feedback [167].”
BackgroundBajinka, O., Ouédraogo, S. Y., Golubnitschaja, O., Li, N., & Zhan, X. (2024) · The EPMA Journal · doi:10.1007/s13167-024-00357-5 · Cited by 26
Characterization of a high-resolution breath acetone meter for ketosis monitoring
Suntrup, D. J., Ratto, T. V., Ratto, M., & McCarter, J. P. (2020) · PeerJ · doi:10.7717/peerj.9969 · Cited by 23
Whitehead, C. E., Ziemke, E. K., Frankowski-McGregor, C. L., Mumby, R. A., Chung, J., Li, J., Osher, N., Coker, O., Baladandayuthapani, V., Kopetz, S., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00781-6 · Cited by 27
“Consistent with this observation, mice treated with MTX-531 do not need to be placed on a ketogenic diet to be active against highly aggressive KPC tumors and may be less susceptible to the insulin-mediated reactivation of PI3K signaling reported for alpelisib 36 .”
InfluentialToward personalized cancer management: Role of precision nutrition–diet interventions
Guo, H., Liu, Y., Wan, T., Da, S., Palanisamy, C. P., Geng, J., Pei, J., Özmen, S., & El‐Aty, A. M. A. (2024) · Journal of Functional Foods · doi:10.1016/j.jff.2024.106584 · Cited by 31
Amaral, L. J., Gresham, G. K., Kim, S., Tighiouart, M., Nelson, T. A., Welborn, A., Lockshon, L., Noorvash, B., Rudnick, J. D., Irwin, S. A., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-06675-6 · Cited by 22
“Limiting glycolytic flux by following KD, therefore, may have anti-cancer effects, including abrogation of the insulin-PI3K signaling pathway that is aberrantly activated in most GBMs 20,21 , and facilitation of an anti-tumor immune response 22–24 .”
Buchanan, C. M., Lee, K., & Shepherd, P. (2019) · Biomolecules · doi:10.3390/biom9090402 · Cited by 25
“This strongly suggests that some degree of feedback compensation is occurring over time, a finding that has been supported by a recent study that actively targeted this feedback loop using dietary and pharmacological strategies to improve the efficacy of PI3K inhibition in the treatment of tumor-bearing mice [87].”
BackgroundResultInfluentialCollins, G. P., Eyre, T. A., Schmitz-Rohmer, D., Townsend, W. M., Popat, R., Giulino-Roth, L. G., Fields, P. A., Krasniqi, F., Soussain, C., Stathis, A., et al. (2021) · HemaSphere · doi:10.1097/hs9.0000000000000656 · Cited by 22
Type-2 diabetes mellitus-associated cancer risk: In pursuit of understanding the possible link
Vulichi, S. R., Runthala, A., Nagaraju, B., Kumar, R., Chunduri, V. R., Kapur, S., Chippada, A. R., & Sistla, D. S. M. (2022) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2022.102591 · Cited by 23
Xiao, Q., Deng, B., Akbari, A., Liu, Q., & Zhu, B. (2022) · Journal of Food Biochemistry · doi:10.1111/jfbc.14407 · Cited by 22
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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