Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Abstract

Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

Keywords: cancer metabolism; kinase inhibitors; mTOR in immunotherapy; mTOR inhibitors; mTOR signaling; mTORC1; mTORC2; metabolism; nutrient metabolism; rapalogs.

Figure 1

mTOR Signaling. mTORC1 activation is modulated by the presence of nutrients such as amino acids at the membrane surface of organelles such as the lysosomes and Golgi. Signaling to mTORC1 is potentiated by growth factor/PI3K signaling via Akt. mTORC2 activation is enhanced by the presence of growth factors and also occurs on membrane subcellular compartments. It is also augmented by G-protein coupled receptor (GPCR) signaling and by nutrient-limiting conditions. The bold lines indicate signals from growth factor signaling. The dashed lines indicate indirect modulation.

Figure 2

The role of mTOR in protein synthesis. mTOR controls several aspects of protein synthesis, including ribosome biogenesis, translation, and amino acid transport and synthesis.

Figure 3

The role of mTOR in glucose metabolism. mTORC1 controls glycolysis via HIF1α and MYC. Through these transcription factors, it promotes the expression of genes whose products are involved in glucose metabolism including glucose transporters and glycolytic enzymes. mTORC2 also has a positive role in the regulation of glucose metabolism. The mTORC2 target, Akt, modulates glucose transport and phosphorylates glycolytic enzymes.

Figure 4

The role of mTOR in fatty acid and lipid synthesis. mTOR controls metabolic enzymes involved in fatty acid and lipid synthesis via SREBP1 and SRPK2. They also modulate expression of fatty acid transporters such as CD36 and carnitine palmitoyl transferase 1c (CPT1c).

Figure 5

The role of mTOR in glutamine metabolism and hexosamine biosynthesis. mTORC1 promotes glutaminolysis and is active in the presence of sufficient glutamine. On the other hand, mTORC2 activation is enhanced when glutamine catabolite levels diminish to promote flux through the hexosamine biosynthesis pathway via control of GFAT1.

Figure 6

The role of mTOR in the pentose phosphate pathway and nucleotide synthesis. mTOR modulates the expression of the enzymes involved in the pentose phosphate pathway, purine and pyrimidine synthesis.