Shukla, Surendra KPurohit, VineeMehla, KamiyaGunda, VenugopalChaika, Nina VVernucci, EnzaKing, Ryan JAbrego, JaimeGoode, Gennifer DDasgupta, AneeshaIllies, Alysha LGebregiworgis, TeklabDai, BingbingAugustine, Jithesh JMurthy, DivyaAttri, Kuldeep SMashadova, OksanaGrandgenett, Paul MPowers, RobertLy, Quan PLazenby, Audrey JGrem, Jean LYu, FangMatés, José MAsara, John MKim, Jung-WhanHankins, Jordan HWeekes, ColinHollingsworth, Michael ASerkova, Natalie JSasson, Aaron RFleming, Jason BOliveto, Jennifer MLyssiotis, Costas ACantley, Lewis CBerim, LyudmylaSingh, Pankaj K2023-01-252023-01-252017http://hdl.handle.net/10668/11393Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.enHIF-1αMUC1cancer metabolismchemotherapy resistancegemcitabinemucinnon-oxidative pentose phosphate pathwaynucleotide synthesispancreatic cancerpyrimidine biosynthesisCarbonDeoxycytidineDigoxinDrug Resistance, NeoplasmGlucoseHumansHypoxia-Inducible Factor 1, alpha SubunitMucin-1Pancreatic NeoplasmsPentose Phosphate PathwayPrognosisPyrimidinesSignal TransductionGemcitabineresearch article28697344open access10.1016/j.ccell.2017.06.0041878-3686PMC5533091http://www.cell.com/article/S1535610817302544/pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533091/pdf