Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism

Douglas E. Biancur, Joao A. Paulo, Beata Małachowska, Maria Quiles Del Rey, Cristovão M. Sousa, Xiaoxu Wang, Albert S. W. Sohn, Gerald C. Chu, Steven P. Gygi, J. Wade Harper, Wojciech Fendler, Joseph D. Mancias () and Alec C. Kimmelman ()
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Douglas E. Biancur: Dana-Farber Cancer Institute
Joao A. Paulo: Harvard Medical School
Beata Małachowska: Medical University of Lodz
Maria Quiles Del Rey: Dana-Farber Cancer Institute
Cristovão M. Sousa: Dana-Farber Cancer Institute
Xiaoxu Wang: Dana-Farber Cancer Institute
Albert S. W. Sohn: Perlmutter Cancer Center, NYU Medical School
Gerald C. Chu: Brigham and Women’s Hospital, Harvard Medical School
Steven P. Gygi: Harvard Medical School
J. Wade Harper: Harvard Medical School
Wojciech Fendler: Dana-Farber Cancer Institute
Joseph D. Mancias: Dana-Farber Cancer Institute
Alec C. Kimmelman: Dana-Farber Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15965

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