TY - JOUR T1 - Increased glucose availability sensitizes pancreatic cancer to chemotherapy JF - bioRxiv DO - 10.1101/2022.04.29.490090 SP - 2022.04.29.490090 AU - Ali Vaziri-Gohar AU - Jonathan J. Hue AU - Hallie G. Graor AU - Ata Abbas AU - Mehrdad Zarei AU - Omid Hajihassani AU - George Titomihelakis AU - John Feczko AU - Moeez Rathore AU - Rui Wang AU - Mahsa Zarei AU - Maryam Goudarzi AU - Renliang Zhang AU - Belinda Willard AU - Li Zhang AU - Gi-Ming Wang AU - Curtis Tatsuoka AU - Joseph M. Salvino AU - Ilya Bederman AU - Henri Brunengraber AU - Costas A. Lyssiotis AU - Jonathan R. Brody AU - Jordan M. Winter Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/05/01/2022.04.29.490090.abstract N2 - Pancreatic cancer (Pancreatic Ductal Adenocarcinoma; PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, leaving chemotherapy as the best available systematic treatment. The discovery of safe and available adjuncts that improve chemotherapeutic efficacy would potentially improve survival outcomes. We show that a hyperglycemic state enhances the efficacy of conventional single- and multi-agent chemotherapies against PDAC. Molecular analyses of tumors exposed to relatively high glucose levels revealed that a key metabolic pathway, glutathione biosynthesis, is diminished and underlies chemo-sensitization by enhancing oxidative injury to cancer cells. Inhibition of this pathway under normal conditions phenocopied a hyperglycemic state by enhancing chemotherapeutic efficacy in mouse PDAC, while rescuing the pathway under high glucose abrogated the anti-tumor effects observed with chemotherapy.Competing Interest StatementC.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 the GOT1-pathway as a therapeutic approach. J.M.S. is a co-author on patents of 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 September 24, 2020: Methods for Treating Wild Type Isocitrate Dehydrogenase 1 Cancers. Information regarding this patent application is as follows: PCT/US20/52445 filed 09/24/20, Claiming Priority to US 62/911,717 filed 10/7/19, File Nos: UHOSP-19738 | 2019-014. ER -