ArticleNeuro-oncology2023
Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma.
Article in Neuro-oncology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 30 citations in OpenAlex.
- Exploring the landscape of targetable alterations in patients with glioblastoma.Nature reviews. Clinical oncology · 2026Review
- Insulin receptor substrate 2 (IRS2) confers resistance to PI3K pathway inhibition in PIK3CA mutant breast cancer.The Journal of biological chemistry · 2026Article
- Metabolic adaptations of the tumor macroenvironment and their role in cancer progression and survivorship.Genes & development · 2026Review
- Benefits and challenges of adding BKM120 to a BI-3406 plus trametinib combination therapy.BMC cancer · 2026Article
- A renaissance in targeting the PI3K/AKT/mTOR pathway.Nature reviews. Drug discovery · 2026Review
- The functional imperative in high-grade glioma.Experimental & molecular medicine · 2026Review
- Beyond base camp: PI3K/mTOR inhibition for the treatment of pediatric high-grade gliomas.Neuro-oncology · 2025Review
- Drug resistant glioblastoma stem cells exhibit enriched stemness signatures and share extracellular matrix overexpression.BMC cancer · 2025Article
- Medical comorbidities prognosticate survival in glioblastoma.BJC reports · 2025Article
- Impact of non-alcoholic hepatic steatosis on prognosis and clinical outcomes in gastric cancer patients undergoing laparoscopic distal gastrectomy.World journal of gastrointestinal surgery · 2025Article
- Beyond Base Camp: Promise and Pitfalls of PI3K/mTOR Inhibition in Pediatric High- Grade Gliomas.Research square · 2025Article
- Ketogenic diet and cancer: multidimensional exploration and research.Science China. Life sciences · 2025Review
- Navigating Glioma Complexity: The Role of Abnormal Signaling Pathways in Shaping Future Therapies.Biomedicines · 2025Review
- Glutamate dehydrogenase 1-catalytic glutaminolysis feedback activates EGFR/PI3K/AKT pathway and reprograms glioblastoma metabolism.Neuro-oncology · 2025Article
- Mapping chromatin remodelling in glioblastoma identifies epigenetic regulation of key molecular pathways and novel druggable targets.BMC biology · 2025Article
- Article
- Towards Effective Treatment of Glioblastoma: The Role of Combination Therapies and the Potential of Phytotherapy and Micotherapy.Current issues in molecular biology · 2024Review
- Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.BMC medicine · 2024Review
- Evolution of Molecular Biomarkers and Precision Molecular Therapeutic Strategies in Glioblastoma.Cancers · 2024Review
- Sex Matters-Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer.Cancers · 2024Article
Corrections and comments
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Authors and funding
17 authors at 5 institutions in 3 countries.
Funding
Abstract
backgroundInsulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM.
methodsThe effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM.
resultsWe found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients.
conclusionReducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.