Exploiting Metabolic Vulnerabilities of Cancer with Precision and Accuracy

Abstract

Links between oncogenic drivers and cancer cell metabolism have emerged over the past several decades, indicating that constitutive oncogenic growth signaling can render cancers susceptible to metabolic interventions. While significant progress has been achieved in the identification of metabolic vulnerabilities of cancer cells, the complexity of the tumor microenvironment (TME) and the dynamic nature of organismal circadian metabolism challenge the precision of targeting cancer metabolism. Here current progress in the areas of cancer metabolism and TME metabolism is reviewed, highlighting how cancer metabolism can be accurately and precisely targeted.

Figure 1

Overview of Cellular Metabolic Pathways, Central metabolic pathways and their connections are outlined, including glycolysis, the TCA cycle, nucleic acid synthesis, lipid synthesis, and the urea cycle. Cancer cells utilize these pathways to varying extents depending on the genetics and tissue of origin of the tumor, as discussed in the main text. Glucose and glutamine can both converted into substrates that can be oxidized via the TCA cycle, but intermediates of these pathways can be diverted to provide substrates for nucleic acid and amino acid synthesis or to replenish TCA cycle intermediates. Glucose can also be converted to lactate and exported (the Warburg Effect). Alternatively, lactate can also be taken up and oxidized as fuel.

Figure 2

Metabolism in the Tumor Microenvironment, In addition to tumor cells, the tumor microenvironment is composed of fibroblasts, macrophages, myeloid-derived suppressor cells, regulatory and cytotoxic T cells, and endothelial cells, among others. These cells depend on specific metabolic substrates for appropriate function, which can be disrupted in the TME or with therapy. Cancer cells can reprogram these cells to produce fuels such as lactate, alanine, and fatty acids that are then consumed by the cancer cells themselves. They can also produce immunosuppressive metabolites, including lactate, adenosine, and kynurenine.