Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors
Year: 2022
Type: article
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.
Source: Nature Cancer
Authors: Ali Vaziri-Gohar, Joel Cassel, Farheen S. Mohammed, Mehrdad Zarei, Jonathan J. Hue, Omid Hajihassani, Hallie J. Graor, Yellamelli V. V. Srikanth, Saadia A. Karim, Ata Abbas, Erin Prendergast, Vanessa Chen, Erryk S. Katayama, Katerina Dukleska, Imran Khokhar, Anthony Andren, Li Zhang, Chunying Wu, Bernadette Erokwu, Chris A. Flask, Mahsa Zarei, Rui Wang, Luke D. Rothermel, Andrea M. P. Romani, Jessica Bowers, Robert Getts, Curtis Tatsuoka, Jennifer P. Morton, Ilya Bederman, Henri Brunengraber, Costas A. Lyssiotis, Joseph M. Salvino, Jonathan R. Brody, Jordan M. Winter
Institutions: Case Comprehensive Cancer Center, Case Western Reserve University, The Wistar Institute, University Hospitals of Cleveland, University Hospitals Cleveland Medical Center, Texas A&M University, Cancer Research UK Scotland Institute, Thomas Jefferson University, University of Michigan, Michigan Medicine, Bioarray Genetics (United States), University of Glasgow, Oregon Health & Science University, OHSU Knight Cancer Institute
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,390
Funders: U.S. Department of Health and Human Services, Case Western Reserve University, Case Comprehensive Cancer Center, Case Western Reserve University, Gateway Foundation, Cancer Research UK, National Institutes of Health, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1192980948, G1205944464, G1273157147, G1390870092, G1736771091, Dynamic Metabolomics via Isotopomer Analysis, G3669178909, Stromal metabolism promotes therapeutic resistance in pancreatic cancer, Purchase of an Echo 650 acoustic liquid handler with Access workstation, Targeting HuR to improve a synthetic lethal therapy for pancreatic cancer, G6097825309, Targeting metabolic stress to induce pancreatic tumor cell death, IDH1 is a novel therapeutic target in pancreatic cancer, G7228899597, G7254500418, Targeting pancreatic cancer's metabolic addiction to HuR, Case GI SPORE, Case Comprehensive Cancer Center Support Grant, University of Michigan Rogel Cancer Center Support Grant 2023-2028, Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic Cancer, Consolidated Basic Cancer Research Program, Mechanisms of metabolic reprogramming by PIK3CA oncogenic mutations
OpenAlex ID: W4282931052