2. Academic Validation
  3. Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism

Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism

  • Nat Commun. 2017 Jul 3;8:15965. doi: 10.1038/ncomms15965.
Douglas E Biancur 1 2,  Joao A Paulo 3,  Beata Małachowska 4 5,  Maria Quiles Del Rey 1,  Cristovão M Sousa 1,  Xiaoxu Wang 1,  Albert S W Sohn 2,  Gerald C Chu 6,  Steven P Gygi 3,  J Wade Harper 3,  Wojciech Fendler 1 4,  Joseph D Mancias 1 3,  Alec C Kimmelman 1 2
Affiliations

Affiliations

  • 1 Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
  • 2 Perlmutter Cancer Center, Department of Radiation Oncology, NYU Medical School, New York, New York 10016, USA.
  • 3 Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 4 Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz 91-738, Poland.
  • 5 Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw 02-091, Poland.
  • 6 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
PMID: 28671190 DOI: 10.1038/ncomms15965
Abstract

Pancreatic ductal adenocarcinoma is a notoriously difficult-to-treat Cancer and patients are in need of novel therapies. We have shown previously that these tumours have altered metabolic requirements, making them highly reliant on a number of adaptations including a non-canonical glutamine (Gln) metabolic pathway and that inhibition of downstream components of Gln metabolism leads to a decrease in tumour growth. Here we test whether recently developed inhibitors of Glutaminase (GLS), which mediates an early step in Gln metabolism, represent a viable therapeutic strategy. We show that despite marked early effects on in vitro proliferation caused by GLS inhibition, pancreatic Cancer cells have adaptive metabolic networks that sustain proliferation in vitro and in vivo. We use an integrated metabolomic and proteomic platform to understand this adaptive response and thereby design rational combinatorial approaches. We demonstrate that pancreatic Cancer metabolism is adaptive and that targeting Gln metabolism in combination with these adaptive responses may yield clinical benefits for patients.

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