Targeting glutaminase and mTOR

Comprehensive genomic and proteomic analyses demonstrate that there is nearly universal activation of the PI3K pathway in glioblastoma (GBM) patients [1]. Persistent PI3K signaling promotes GBM formation and tumor progression in genetic mouse models, establishing PI3K and its effecter mTOR as compelling molecular targets. mTOR, which has two distinct complexes, mTORC1 and mTORC2, is a protein kinase that integrates oncogenic signaling from growth factor receptors through PI3K, with cellular energy and nutrient status, to activate downstream signaling pathways that promote tumor growth and survival. Despite the perceived importance of mTOR as a molecular target in GBM, early-phase clinical trials using the mTOR inhibitor rapamycin failed to show efficacy. This result was potentially related to feedback activation of PI3K/Akt signaling and homeostatic regulation of other critical signals and cellular metabolism [2]. Oncogenic signaling pathways directly promote metabolic reprogramming to upregulate the biosynthesis of proteins, nucleotides, amino acids and lipids, required for the enhanced growth of cancer cells. These alterations include aerobic glycolysis known as the Warburg effect, which provides cancer cells selective advantages through enhanced catabolism of glutamine [3]. Glutamine is catabolized to α-ketoglutarate (αKG), an intermediate of the tricarboxylic acid (TCA) cycle, through two deamination reactions in a process termed glutamine anaplerosis. The first reaction requires glutaminase (GLS) to generate glutamate. The second reaction requires either glutamate dehydrogenase (GDH) or transaminases. Cancer cells usually display persistent TCA cycle activity despite robust aerobic glycolysis and often require mitochondrial catabolism of glutamine to TCA cycle intermediates to maintain rapid proliferation. Therefore, elucidating the role of glutamine metabolism could lead to significantly more effective targeted therapies for cancers. We recently examined the role of glutamine metabolism in response to mTOR-targeted treatments for GBM [4]. Surprisingly, mTOR-targeted treatments affected metabolic reprogramming and increased GLS expression to deliver glutamine carbon to the TCA cycle, revealing that GBM cells were strongly addicted to glutamine. This compensatory glutamine metabolism allowed GBM cells to survive mTOR inhibitor treatment and was mediated by regulating the levels of αKG. The suppression of GLS by RNA interference or GLS inhibition with Compound 968 sensitized GBM cells to mTOR-targeted therapies. The combined mTOR and GLS inhibition caused synergic tumor cell death in mouse xenograft models. These results demonstrate that the inhibition of mTOR signaling is sufficient to change the metabolic characteristics of GBM cells. Increasing GLS expression to elevate glutamate levels could be a method of compensating for the loss of TCA …