Abstract 4986: Pancreatic cancers develop metabolic resistance pathways to glutaminase inhibition

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13_Supplement; p. 4986
• Main Authors: Mancias, Joseph D., Biancur, Douglas E., Paulo, Joao A., Rey, Maria Quiles Del, Sousa, Cristovão M., Wang, Xiaoxu, Chu, Gerald C., Gygi, Steven P., Harper, J. Wade, Kimmelman, Alec C.
• Format: Journal Article
• Language: English
• Published: 01.07.2017
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-4986

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognosis. Therefore, novel treatment options are essential to combat this highly refractory disease. Oncogenic Kras can promote a metabolic rewiring of pancreatic cancers, including the non-canonical use of glutamine to support growth and proliferation through redox homeostasis. Indeed, inhibition of downstream components of glutamine metabolism leads to a decrease in tumor growth. The first step in glutamine metabolism is mediated by the enzyme glutaminase (GLS) which catalyzes the conversion of glutamine to glutamate in the mitochondria where, in PDAC, glutamine-derived glutamate is metabolized ultimately resulting in increased reducing potential in the form of increased NADPH and GSH. An outstanding question in pancreatic cancer is whether GLS inhibition is a viable therapeutic strategy given it is the most proximal enzyme in the PDAC-specific glutamine metabolism pathway, and how this may differ from targeting distal parts of the pathway. Using a combination of in vitro and in vivo models of pancreatic cancer, we tested whether recently developed highly potent inhibitors of GLS are an effective therapy for PDAC. We demonstrate that despite dramatic early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that allow them to sustain proliferation in vitro and in vivo. Through an integrated proteomic and metabolomic analysis, we identify multiple compensatory pathways that may explain the resistance to GLS inhibition and show as proof of concept that combining inhibitors to these pathways with GLS inhibitors may have therapeutic utility. Citation Format: Joseph D. Mancias, Douglas E. Biancur, Joao A. Paulo, Maria Quiles Del Rey, Cristovão M. Sousa, Xiaoxu Wang, Gerald C. Chu, Steven P. Gygi, J. Wade Harper, Alec C. Kimmelman. Pancreatic cancers develop metabolic resistance pathways to glutaminase inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4986. doi:10.1158/1538-7445.AM2017-4986