ArticleNature cancer2022
Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
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Article in Nature cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50 citing papers in PubMed, 73 citations in OpenAlex.
- Article
- Targeting Reactive Species Stress and Nutrient Sensing to Enhance NK-Cell Function: Mechanistic Strategies for Overcoming Pancreatic Cancer Progression and Resistance Through Supplement Therapy.International journal of molecular sciences · 2026Review
- Metabolism, autophagy, and cell death: The triangular axis in tumor survival and therapeutic resistance.Redox biology · 2026Review
- Expression Of the Idh1 R132h Protein in Hepatopancreatobiliary Malignancies in A Single Center Population: Immunohistochemical Study.Iranian journal of pathology · 2026Article
- TKTL1 mediates metabolic adaptation and stress resistance in pancreatic cancer cells under nutrient-deprived conditions.Oncogene · 2026Article
- Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.Acta neuropathologica · 2026Article
- Article
- Increased Glucose Availability Sensitizes Pancreatic Cancer to Macrophage-Targeting Immunotherapies.Cancer research communications · 2026Article
- Antitumor immunotoxin expression is enhanced by Escherichia coli csrB-promoter activity.Oncogene · 2026Article
- N-Acetylneuraminate Pyruvate Lyase Promotes Cell Adaptation to Glucose Deprivation by Regulating Intracellular ATP Levels.Current issues in molecular biology · 2026Article
- A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.Cell reports. Medicine · 2026Article
- The allosteric IDH1 inhibitor ivosidenib overcomes chemoresistance in intrahepatic cholangiocarcinoma models expressing wild-type IDH1.The Journal of clinical investigation · 2026Article
- Impact of diabetes mellitus on treatment efficacy in patients with advanced pancreatic cancer: the Italian, multicenter, observational PANCAKE study.ESMO gastrointestinal oncology · 2026Article
- Single-cell multi-omics identifies metabolism-linked epigenetic reprogramming as a driver of therapy-resistant medulloblastoma.Nature communications · 2025Article
- The integral membrane protein smim4 modulates redox balance via malate compartmentalization in pancreatic cancer.Nature communications · 2025Article
- What's on the menu?: metabolic constraints in the pancreatic tumor microenvironment.The Journal of clinical investigation · 2025Review
- Metabolic Reprogramming of Anti-cancer T Cells: Targeting AMPK and PPAR to Optimize Cancer Immunotherapy.Indian journal of clinical biochemistry : IJCB · 2025Review
- Weight Management for Fertility-Preservation Therapy in Endometrial Cancer: Opportunities and Challenges.Current oncology reports · 2025Review
- BBOX1 restrains TBK1-mTORC1 oncogenic signaling in clear cell renal cell carcinoma.Nature communications · 2025Article
- Allogeneic CD33-directed CAR-NKT cells for the treatment of bone marrow-resident myeloid malignancies.Nature communications · 2025Article
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Authors and funding
34 authors at 7 institutions in 2 countries.
Ali Vaziri-GoharCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
Joel CasselMolecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
Farheen S MohammedMolecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
Mehrdad ZareiCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
Jonathan J HueCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
Omid HajihassaniCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
Hallie J GraorCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
Yellamelli V V SrikanthMolecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
Saadia A KarimCancer Research UK Beatson Institute, Glasgow, UK.ORCID http://orcid.org/0000-0002-3727-0667
Ata AbbasCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.ORCID http://orcid.org/0000-0001-8272-1853
Erin PrendergastDepartment of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
Vanessa ChenDepartment of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
Erryk S KatayamaCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.ORCID http://orcid.org/0000-0002-2206-8124
Katerina DukleskaJefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Imran KhokharJefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Anthony AndrenDepartment of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Li ZhangDepartment of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Chunying WuDepartment of Radiology, Case Western Reserve University, Cleveland, OH, USA.
Bernadette ErokwuDepartment of Radiology, Case Western Reserve University, Cleveland, OH, USA.
Chris A FlaskDeptartments of Radiology, Biomedical Engineering, and Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
Mahsa ZareiDepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA.
Rui WangCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
Luke D RothermelDepartment of Surgery, Division of Surgical Oncology, University Hospitals, Cleveland Medical Center, Cleveland, OH, USA.
Andrea M P RomaniDepartment of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA.
Jessica BowersCode Biotherapeutics Inc, Hatfield, PA, USA.
Robert GettsCode Biotherapeutics Inc, Hatfield, PA, USA.
Curtis TatsuokaDepartment of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
Jennifer P MortonCancer Research UK Beatson Institute, Glasgow, UK.
Ilya BedermanDepartment of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
Henri BrunengraberDepartment of Nutrition and Biochemistry, Case Western Reserve University, Cleveland, OH, USA.
Costas A LyssiotisDepartment of Molecular and Integrative Physiology, University of Michigan School of Medicine, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-9309-6141
Joseph M SalvinoMolecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-2184-5980
Jonathan R BrodyBrenden Colson Center for Pancreatic Care; Departments of Surgery and Cell, Developmental & Cancer Biology; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
Jordan M WinterCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA. jordan.winter@UHhospitals.org.ORCID http://orcid.org/0000-0002-5200-6557
Case Western Reserve University · USUniversity Hospitals of Cleveland · USThe Wistar Institute · USMichigan Medicine · USCancer Research UK Scotland Institute · GBThomas Jefferson University · USOregon Health & Science University · US
Funding
XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Alexey I Nesvizhskii · 1988 to 2026
$178.2MTUMOR METABOLISM PROGRAMP30CA043703 · NCI · CASE WESTERN RESERVE UNIVERSITY · PI Amar Desai · 1987 to 2026
$142.3MTumor Microenvironment and MetastasisP30CA010815 · NCI · WISTAR INSTITUTE · PI Luis J Montaner · 1985 to 2026
$75.9MTargeting 15-PGDH in Colon Cancer Prognosis, Prediction, Treatment and PreventionP50CA150964 · NCI · CASE WESTERN RESERVE UNIVERSITY · PI MARKOWITZ, SANFORD D. · 2011 to 2022
$24.6MDynamic Metabolomics via Isotopomer Analysis(RMI)R33DK070291 · NIDDK · CASE WESTERN RESERVE UNIVERSITY · PI BRUNENGRABER, HENRI · 2004 to 2006
$3.3MMechanisms of metabolic reprogramming by PIK3CA oncogenic mutationsR01CA196643 · NCI · CASE WESTERN RESERVE UNIVERSITY · PI Zhenghe Wang · 2016 to 2026
$3.1MTargeting pancreatic cancer's metabolic addiction to HuRR37CA227865 · NCI · CASE WESTERN RESERVE UNIVERSITY · PI WINTER, JORDAN M · 2018 to 2024
$2.7MIntratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic CancerR37CA237421 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Costas Andreas Lyssiotis · 2020 to 2026
$2.6MStromal metabolism promotes therapeutic resistance in pancreatic cancerR01CA248160 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LYSSIOTIS, COSTAS ANDREAS · 2020 to 2024
$2.0MTargeting metabolic stress to induce pancreatic tumor cell deathR01CA244931 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LYSSIOTIS, COSTAS ANDREAS · 2020 to 2024
$1.9MTargeting HuR to improve a synthetic lethal therapy for pancreatic cancerR01CA212600 · NCI · THOMAS JEFFERSON UNIVERSITY · PI BRODY, JONATHAN · 2017 to 2021
$1.9MPurchase of an Echo 650 acoustic liquid handler with Access workstationS10OD030245 · OD · WISTAR INSTITUTE · PI SALVINO, JOSEPH M · 2021 to 2021
$567kCancer Research UK 29996NCI NIH HHS F32 CA247466NCI NIH HHS P30 CA010815NCI NIH HHS P30 CA043703NCI NIH HHS P30 CA046592NCI NIH HHS P50 CA150964NCI NIH HHS R01 CA196643NCI NIH HHS R01 CA212600NCI NIH HHS R01 CA244931NCI NIH HHS R01 CA248160NCI NIH HHS R37 CA227865NCI NIH HHS R37 CA237421NIDDK NIH HHS R33 DK070291NIH HHS S10 OD030245
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.
Indexed as
Isocitrate DehydrogenasePancreatic NeoplasmsAllosteric RegulationEnzyme InhibitorsHumansMutationNutrientsTumor MicroenvironmentEnzyme InhibitorsIDH1 protein, humanIsocitrate DehydrogenaseNutrients
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