PT  - JOURNAL ARTICLE
AU  - Ali Vaziri-Gohar
AU  - Jonathan J. Hue
AU  - Hallie J. Graor
AU  - Erin Prendergast
AU  - Vanessa Chen
AU  - Joel Cassel
AU  - Farheen S. Mohammed
AU  - Ata Abbas
AU  - Katerina Dukleska
AU  - Imran Khokhar
AU  - Omid Hajhassani
AU  - Mahsa Zarei
AU  - Rui Wang
AU  - Luke D. Rothermel
AU  - Ilya Bederman
AU  - Jessica Browers
AU  - Robert Getts
AU  - Henri Brunengraber
AU  - Joseph M. Salvino
AU  - Jonathan R. Brody
AU  - Jordan M. Winter
TI  - Cancer cells are sensitive to wild-type IDH1 inhibition under nutrient limitation
AID  - 10.1101/2020.11.19.390633
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.19.390633
4099  - http://biorxiv.org/content/early/2020/11/20/2020.11.19.390633.short
4100  - http://biorxiv.org/content/early/2020/11/20/2020.11.19.390633.full
AB  - Pancreatic cancer cells alter their metabolism to survive cancer-associated stress (1-4). For example, cancer cells must adapt to steep nutrient gradients that characterize the natural tumor microenvironment (TME) (5-7). In the absence of adaptive strategies, harsh metabolic conditions promote the generation of free radicals (8) 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 alpha-ketoglutarate, and uses NADP(H) as a cofactor. We show that under low nutrient conditions, the enzymatic reaction favors oxidative decarboxylation to yield NADPH and alpha-ketoglutarate. Metabolic studies showed that the IDH1 products directly support antioxidant defense and mitochondrial function in stressed cancer cells. Genetic IDH1 suppression reduced growth of pancreatic cancer cells in vitro under low nutrient conditions and in mouse models of pancreatic cancer. Surprisingly, allosteric inhibitors of mutant IDH1 proved to be potent wild-type IDH1 inhibitors under conditions specific to the TME, highlighting a natural therapeutic window. The presence of low magnesium enhanced allosteric inhibition by the drug, and ambient low glucose levels enhanced cancer cells’ dependence on wild-type IDH1. Thus, intrinsic TME 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, for the treatment of multiple wild-type IDH1 cancers (e.g., pancreatic).Competing Interest StatementJordan Winter, along with University Hospitals, filed the following patent application on September 24, 2020: Methods for Treating Wild Type Isocitrate Dehydrogenase 1 Cancer (PCT/US20/52445 filed 09/24/2020, Claiming Priority to US 62/911,717 filed 10/7/2019, File Nos: UHOSP-19738, 2019-014). Robert Getts is an inventor on multiple issued patents and patent applications covering the manufacture and use of 3DNA technology as part of his role in Genisphere LLC. He is also as employee and officer of the Genisphere LLC and has stock and stock options.