In conclusion, this study identified alanine and NAD biosynthetic pathways as two epistatic targets of interventions to decrease energetic and proliferative fitness of SDH-deficient cells and, as a consequence, unraveled a metabolic condition enhancing the anti-tumor effects of pharmacological NAMPT inhibition, thereby paving the way for the clinical translation of a novel and effective drug approach against malignancies. The gene discussed is SDHB; the disease is neoplasm.