ArticleCancer & metabolism2015
Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone.
Article in Cancer & metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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89 citing papers in PubMed, 140 citations in OpenAlex.
- Stress adaptation pathways and HA-CD44 signaling maintain the survival of pancreatic cancer cells with centrosome amplification.Cell communication and signaling : CCS · 2026Article
- In Vitro Evaluation of Natural Sesquiterpene Lactones and Naphthoquinones Against Pancreatic Ductal Adenocarcinoma Cells.Molecules (Basel, Switzerland) · 2026Article
- Reactive oxygen species (ROS) in cancer: from mechanism to therapeutic implications.Signal transduction and targeted therapy · 2026Review
- Metabolic characteristics in hepatocellular carcinoma: amino acid metabolic reprogramming.Molecular cancer · 2026Review
- Targeting Glutamine Metabolic Reprogramming in Pancreatic Cancer: Current Insights and Future Directions.Current cancer drug targets · 2026Review
- Controlled Self-Immolative Release of β-Lapachone via an OptimizedJournal of the American Chemical Society · 2025Article
- Multi-omics revealed GOT1/ALDH3A1 pathway attenuated head and neck squamous cell carcinoma and increased cisplatin sensitivity through ROS induced by mitochondrial dysfunction.Redox report : communications in free radical research · 2025Article
- NRF2 immunobiology in cancer: implications for immunotherapy and therapeutic targeting.Oncogene · 2025Review
- GOT2: New therapeutic target in pancreatic cancer.Genes & diseases · 2025Review
- The role of AMPK in pancreatic cancer: from carcinogenesis to treatment.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025Review
- GOT2: a moonlighting enzyme at the crossroads of cancer metabolism and theranostics.Frontiers in immunology · 2025Review
- Emerging mechanisms and promising approaches in pancreatic cancer metabolism.Cell death & disease · 2024Review
- Deciphering glutamine metabolism patterns for malignancy and tumor microenvironment in clear cell renal cell carcinoma.Clinical and experimental medicine · 2024Article
- HuR controls glutaminase RNA metabolism.Nature communications · 2024Article
- Glutamine metabolism, a double agent combating or fuelling hepatocellular carcinoma.JHEP reports : innovation in hepatology · 2024Review
- Circular RNA Dipeptidyl Peptidase 4 (circDPP4) Stimulates the Expression of Glutamate Dehydrogenase 1 to Contribute to the Malignant Phenotypes of Prostate Cancer by Sponging miR-497-5p.Molecular biotechnology · 2024Article
- The role of GOT1 in cancer metabolism.Frontiers in oncology · 2024Review
- The Role of NQO1 in Ovarian Cancer.International journal of molecular sciences · 2023Review
- Single-Cell Kinetic Modeling of β-Lapachone Metabolism in Head and Neck Squamous Cell Carcinoma.Antioxidants (Basel, Switzerland) · 2023Article
- Spotlight on GOT2 in Cancer Metabolism.OncoTargets and therapy · 2023Review
29 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 6 institutions in 1 country.
Funding
Abstract
backgroundPancreatic ductal adenocarcinomas (PDA) activate a glutamine-dependent pathway of cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) production to maintain redox homeostasis and support proliferation. Enzymes involved in this pathway (GLS1 (mitochondrial glutaminase 1), GOT1 (cytoplasmic glutamate oxaloacetate transaminase 1), and GOT2 (mitochondrial glutamate oxaloacetate transaminase 2)) are highly upregulated in PDA, and among these, inhibitors of GLS1 were recently deployed in clinical trials to target anabolic glutamine metabolism. However, single-agent inhibition of this pathway is cytostatic and unlikely to provide durable benefit in controlling advanced disease.
resultsHere, we report that reducing NADPH pools by genetically or pharmacologically (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) or CB-839) inhibiting glutamine metabolism in mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) PDA sensitizes cell lines and tumors to ß-lapachone (ß-lap, clinical form ARQ761). ß-Lap is an NADPH:quinone oxidoreductase (NQO1)-bioactivatable drug that leads to NADPH depletion through high levels of reactive oxygen species (ROS) from the futile redox cycling of the drug and subsequently nicotinamide adenine dinucleotide (NAD)+ depletion through poly(ADP ribose) polymerase (PARP) hyperactivation. NQO1 expression is highly activated by mutant KRAS signaling. As such, ß-lap treatment concurrent with inhibition of glutamine metabolism in mutant KRAS, NQO1 overexpressing PDA leads to massive redox imbalance, extensive DNA damage, rapid PARP-mediated NAD+ consumption, and PDA cell death-features not observed in NQO1-low, wild-type KRAS expressing cells.
conclusionsThis treatment strategy illustrates proof of principle that simultaneously decreasing glutamine metabolism-dependent tumor anti-oxidant defenses and inducing supra-physiological ROS formation are tumoricidal and that this rationally designed combination strategy lowers the required doses of both agents in vitro and in vivo. The non-overlapping specificities of GLS1 inhibitors and ß-lap for PDA tumors afford high tumor selectivity, while sparing normal tissue.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.