Title | Insulin feedback is a targetable resistance mechanism of PI3K inhibition in glioblastoma. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Noch EK, Palma LN, Yim I, Bullen N, Qiu Y, Ravichandran H, Kim J, Rendeiro A, Davis MB, Elemento O, Pisapia DJ, Zhai K, LeKaye HCarl, Koutcher JA, Wen PY, Ligon KL, Cantley LC |
Journal | Neuro Oncol |
Volume | 25 |
Issue | 12 |
Pagination | 2165-2176 |
Date Published | 2023 Dec 08 |
ISSN | 1523-5866 |
Keywords | Animals, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Feedback, Glioblastoma, Humans, Hyperglycemia, Hypoglycemic Agents, Insulin, Metformin, Mice, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases, Retrospective Studies, Tumor Microenvironment |
Abstract | BACKGROUND: Insulin 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. METHODS: The 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. RESULTS: We 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. CONCLUSION: Reducing 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. |
DOI | 10.1093/neuonc/noad117 |
Alternate Journal | Neuro Oncol |
PubMed ID | 37399061 |
PubMed Central ID | PMC10708938 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States P50 CA165962 / CA / NCI NIH HHS / United States S10 OD023669 / OD / NIH HHS / United States K08 NS128263 / NH / NIH HHS / United States |
Related Faculty:
David Pisapia, M.D.