In cancer, all roads lead to NADPH.

Cancer cells require increased levels of NADPH for increased nucleotide synthesis and for protection from ROS. Recent studies show that increased NADPH is generated in several ways. Activated AKT phosphorylates NAD kinase (NADK), increasing its activity. NADP formed, is rapidly converted to NADPH by glucose 6-phosphate dehydrogenase and malic enzymes, overexpressed in tumor cells with mutant p53. Calmodulin, overexpressed in some cancers, also increases NADK activity. Also, in IDH1/2 mutant cancer, NADPH serves as the cofactor to generate D-2 hydroxyglutarate, an oncometabolite. The requirement of cancer cells for elevated levels of NADPH provides an opportunity to target its synthesis for cancer treatment.