Introduction: The Resurgence of Metabolic Oncology
The concept of metabolic reprogramming, once considered a bystander effect of oncogenic signaling, has moved to the forefront of precision oncology. Central to this shift is the understanding of the Krebs cycle—not just as a bioenergetic hub, but as a source of oncometabolites that drive tumorigenesis through epigenetic and signaling alterations. Mutations in enzymes such as fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase (IDH) lead to the accumulation of metabolites that stabilize hypoxia-inducible factors (HIFs), even in the presence of oxygen. This state of ‘pseudohypoxia’ triggers aggressive angiogenesis and metabolic shifts toward aerobic glycolysis. The BRISK trial (KCSG AL22-16) represents a critical effort to exploit these vulnerabilities using a dual-targeted approach with bevacizumab and erlotinib.
