Metabolic Plasticity in Chemotherapy Resistance

Abstract

Resistance of cancer cells to chemotherapy is the first cause of cancer-associated death. Thus, new strategies to deal with the evasion of drug response and to improve clinical outcomes are needed. Genetic and epigenetic mechanisms associated with uncontrolled cell growth result in metabolism reprogramming. Cancer cells enhance anabolic pathways and acquire the ability to use different carbon sources besides glucose. An oxygen and nutrient-poor tumor microenvironment determines metabolic interactions among normal cells, cancer cells and the immune system giving rise to metabolically heterogeneous tumors which will partially respond to metabolic therapy. Here we go into the best-known cancer metabolic profiles and discuss several studies that reported tumors sensitization to chemotherapy by modulating metabolic pathways. Uncovering metabolic dependencies across different chemotherapy treatments could help to rationalize the use of metabolic modulators to overcome therapy resistance.

Keywords: TCA cycle; Warburg effect; cancer; chemoresistance; metabolic reprogramming; metabolic vulnerabilities.

Figure 1

Common metabolic features targeted in cancer cells. Cancer cells could present enhanced glycolisis and lactate release, enhanced FA (fatty acids) synthesis, uptake and oxidation; enhanced OxPhos activity, enhanced glutamine uptake and metabolism, enhanced branched amino acids (BCAAs) uptake and oxidation, etc. Targeting these pathways could sensitize cancer cells to chemotherapy.

Figure 2

Schematic representation of metabolic alterations involved in the onset of resistance to platinum agents, anthracyclines, taxanes and hormone therapy.