Cancer cells are sensitive to wild-type IDH1 inhibition under nutrient limitation

Pancreatic cancer cells alter their metabolism to survive cancer-associated stress. For example, cancer cells must adapt to steep nutrient gradients that characterize the natural tumor microenvironment. In the absence of adaptive strategies, harsh metabolic conditions promote free radicals and impair energy production in tumor cells. Towards this end, wild-type isocitrate dehydrogenase 1 (IDH1) activity is a metabolic requirement for cancer cells living in a harsh metabolic milieu. The cytosolic enzyme interconverts isocitrate and α-ketoglutarate (αKG) and uses NADP(H) as a cofactor. We show that under low nutrient conditions, the enzymatic reaction favors oxidative decarboxylation to yield NADPH and αKG. Metabolic studies showed that the IDH1 products directly support an antioxidant defense and mitochondrial function in stressed cancer cells. Genetic IDH1 suppression reduced pancreatic cancer cells' growth in vitro under low nutrient conditions and in mouse models of pancreatic cancer. Thus, intrinsic tumor microenvironment conditions sensitized wild-type IDH1 to FDA-approved AG-120 (ivosidenib) and revealed the drug to be a potent single-agent therapeutic in cell culture and diverse in vivo cancer models. This work identified a potentially new repertoire of safe cancer therapies, including a clinically available compound, to treat multiple wild-type IDH1 cancers, including pancreatic cancer. MiaPaCa-2 cells under low glucose for 48 hours (2.5 mM glucose) compared with control (25 mM glucose). Three independent biological replicates were used.