Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment

TLDR

The mechanistic target of rapamycin (mTOR) is hyperactivated in many cancers, yet the metabolic consequences of its inhibition remain poorly understood. The study demonstrates that compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors in glioblastoma multiforme. The authors integrated metabolic and functional studies in GBM cell lines, preclinical models, and clinical samples to investigate this resistance mechanism. Glutaminase activity and glutamate levels rise after mTOR inhibition, GLS promotes GBM survival via α‑ketoglutarate, and dual inhibition of mTOR and GLS synergistically kills tumor cells and suppresses growth, underscoring glutamine metabolism as a key resistance pathway and supporting combination therapy.

Abstract

The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor–dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate–dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.