Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment
Kazuhiro Tanaka, … , Paul S. Mischel, Eiji Kohmura
Kazuhiro Tanaka, … , Paul S. Mischel, Eiji Kohmura
Published March 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1591-1602. https://doi.org/10.1172/JCI78239.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 43

Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment

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.

Authors

Kazuhiro Tanaka, Takashi Sasayama, Yasuhiro Irino, Kumi Takata, Hiroaki Nagashima, Naoko Satoh, Katsusuke Kyotani, Takashi Mizowaki, Taichiro Imahori, Yasuo Ejima, Kenta Masui, Beatrice Gini, Huijun Yang, Kohkichi Hosoda, Ryohei Sasaki, Paul S. Mischel, Eiji Kohmura

×

Figure 1

Glutamine and glutamate levels and GLS expression are elevated in the tumors of GBM patients.

Options: View larger image (or click on image) Download as PowerPoint
Glutamine and glutamate levels and GLS expression are elevated in the tu...
(A) MRS studies targeting glutamine and glutamate for tumors (red) and contralateral normal brain (blue) regions in a 68-year-old patient with GBM. The peaks of choline, glutamine and glutamate complex, and NAA are around 3.22, 2.4, and 2.0 ppm of chemical shift, respectively. Cho, choline; Cr, Creatine; Gln, glutamine; Glu, glutamate. (B) Glutamine and glutamate levels in MRS studies for tumors and contralateral normal brain regions in 12 GBM patients. The relative level of glutamine and glutamate was calculated with respect to creatine and phosphocreatine for VOIs of tumor and contralateral normal brain. *P < 0.05; ***P < 0.001, according to 2-tailed Student’s t test. (C) mRNA levels of key enzymes including GLS and GS between glutamine and glutamate in 12 GBM patients. The relative levels of GLS and GS are presented as the tumor/normal brain (T/N) expression ratio. (D) Immunoblot analysis of GLS staining in tumor and normal brain tissue obtained at tumor resection from 6 patients with GBM. See also Supplemental Figure 1.