Tumor Cell Survival Under Metabolic Stress

Today's targeted therapeutics exert their anti‐cancer effects mainly by blocking molecular signals that promote tumor cell proliferation, obstruct cell death, hamper cellular differentiation, or facilitate angiogenesis. However, the molecular pathways that underlie these cellular processes are multifaceted and often redundant, allowing tumor cells to escape these drugs. Another approach may be to target tumor cell metabolism. In the 1920s, Warburg noted that cancers exhibit increased rates of glycolysis even in the presence of oxygen, a phenomenon known as aerobic glycolysis or the ‘Warburg effect’. The switch from oxidative phosphorylation to glycolysis that underlies the Warburg effect represents an alteration to tumor cell metabolism that permits cancer cells to adapt and thrive in conditions that kill normal cells. Such adaptations may include the upregulation or alteration of molecular pathways to increase energy production, expansion of the cell's biosynthetic capacity, and/or adoption of an enhanced redox state to cope with elevated levels of deleterious reactive oxygen species. Understanding the energy sources and metabolic pathways utilized by cancer cells to survive in a hostile microenvironment should allow the exploitation of this knowledge to design more effective anti‐cancer drugs.