@article{6deeac4e8adf4dc3bdb2f458b69ea92b,
title = "Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors",
abstract = "Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.",
author = "Ali Vaziri-Gohar and Joel Cassel and Mohammed, {Farheen S.} and Mehrdad Zarei and Hue, {Jonathan J.} and Omid Hajihassani and Graor, {Hallie J.} and Srikanth, {Yellamelli V.V.} and Karim, {Saadia A.} and Ata Abbas and Erin Prendergast and Vanessa Chen and Katayama, {Erryk S.} and Katerina Dukleska and Imran Khokhar and Anthony Andren and Li Zhang and Chunying Wu and Bernadette Erokwu and Flask, {Chris A.} and Mahsa Zarei and Rui Wang and Rothermel, {Luke D.} and Romani, {Andrea M.P.} and Jessica Bowers and Robert Getts and Curtis Tatsuoka and Morton, {Jennifer P.} and Ilya Bederman and Henri Brunengraber and Lyssiotis, {Costas A.} and Salvino, {Joseph M.} and Brody, {Jonathan R.} and Winter, {Jordan M.}",
note = "Funding Information: R.G. is an inventor on multiple issued patents and patent applications covering the manufacture and use of 3DNA technology as part of his role in Code Biotherapeutics, Inc. He is also an employee and officer of Code Biotherapeutics, Inc. and has stock and stock options. C.A.L. has received consulting fees from Astellas Pharmaceuticals and Odyssey Therapeutics and is an inventor on patents pertaining to Kras-regulated metabolic pathways, redox control pathways in cancer and targeting of the GOT1-pathway as a therapeutic approach. J.M.S. is a coauthor on patents on IDH1 inhibitors, and has received sponsored research funding from the Barer Institute and patents pending to Wistar Institute. J.M.W., along with University Hospitals, filed the following patent application on 24 September 2020: Methods for Treating Wild Type Isocitrate Dehydrogenase 1 Cancers. Information regarding this patent application is as follows: PCT/US20/52445 filed 24 September 2020, Claiming Priority to US 62/911,717 filed 7 October 2019, file nos: UHOSP-19738 | 2019-014. Funding Information: We thank S. Markowitz for his valuable insights and support; A. Tasdogan and J. Mears for their helpful suggestions with the manuscript; D. Carpizo for generously providing KPC K8484 cells; W. Schiemann for providing luciferase-expressing plasmid; and CWRU Genomic core facility for sequencing assistance. Grant support for this research comes from postdoctoral fellowship grant (no. NCI 1F32CA247466-01, A.V.-G.); NIDDK R33DK070291, NCI R01CA196643 (H.B.), NCI R37CA237421, R01CA248160 and R01CA244931 (C.A.L.); UMCCC Core Grant nos. P30CA046592 (C.A.L.), NCI P30 CA010815-53 and NCI 5 R37 CA227865-04 (J.M.S.); American Cancer Society nos. MRSG-14-019-01-CDD and 134170-MBG-19-174-01-MBG (J.M.W.) and NCI R37CA227865-01A1 (J.M.W.); Case Comprehensive Cancer Center (no. GI SPORE 5P50CA150964-08, J.M.W.); Case Comprehensive Cancer Center P30 Core Grant no. P30CA043703 (J.M.W.); Gateway Foundation for Cancer Research (J.M.W.); and University Hospitals research start-up package (J.M.W.). We are grateful for additional support from numerous donors to the University Hospitals pancreatic cancer research program, including the John and Peggy Garson Family Research Fund, The Jerome A. and Joy Weinberger Family research fund, Robin Holmes-Novak in memory of Eugene, and R. and S. Behar. Publisher Copyright: {\textcopyright} 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",
year = "2022",
month = jul,
doi = "10.1038/s43018-022-00393-y",
language = "English (US)",
volume = "3",
pages = "852--865",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "7",
}