RT Journal Article
SR Electronic
T1 Cancer cells are sensitive to wild-type IDH1 inhibition under nutrient limitation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.19.390633
DO 10.1101/2020.11.19.390633
A1 Ali Vaziri-Gohar
A1 Jonathan J. Hue
A1 Hallie J. Graor
A1 Erin Prendergast
A1 Vanessa Chen
A1 Joel Cassel
A1 Farheen S. Mohammed
A1 Ata Abbas
A1 Katerina Dukleska
A1 Imran Khokhar
A1 Omid Hajhassani
A1 Mahsa Zarei
A1 Rui Wang
A1 Luke D. Rothermel
A1 Ilya Bederman
A1 Jessica Browers
A1 Robert Getts
A1 Henri Brunengraber
A1 Joseph M. Salvino
A1 Jonathan R. Brody
A1 Jordan M. Winter
YR 2020
UL http://biorxiv.org/content/early/2020/11/20/2020.11.19.390633.abstract
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.