Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling

Cancer & Metabolism

Seth J. Parker¹  Christian M. Metallo¹  Anna Maria Colangelo²  Lilia Alberghina²  Marcella Bonanomi²  Rohit Bharat²  Marco Vanoni²  Nicole Righi²  Federica Conte³  Federico Papa³  Giulia Fiscon³  Paola Paci⁴  Ingrid Cifola⁵  Tania Camboni⁵  Marilena Ripamonti⁶  Elisabetta Napodano⁶  Daniela Gaglio⁶  Rosa Maria Moresco⁷  Silvia Valtorta⁷  Isabella Raccagni⁸ 

[1] Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA;Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA;ISBE. IT/Centre of Systems Biology, Piazza della Scienza 4, 20126, Milan, Italy;Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy;ISBE. IT/Centre of Systems Biology, Piazza della Scienza 4, 20126, Milan, Italy;Institute for Systems Analysis and Computer Science “Antonio Ruberti”, National Research Council, Rome, Italy;ISBE. IT/Centre of Systems Biology, Piazza della Scienza 4, 20126, Milan, Italy;Institute for Systems Analysis and Computer Science “Antonio Ruberti”, National Research Council, Rome, Italy;Department of Computer, Control and Management Engineering, Sapienza University of Rome, Rome, Italy;Institute for Biomedical Technologies (ITB), National Research Council (CNR), Segrate, Milan, Italy;Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, MI, Italy;ISBE. IT/Centre of Systems Biology, Piazza della Scienza 4, 20126, Milan, Italy;Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, MI, Italy;ISBE. IT/Centre of Systems Biology, Piazza della Scienza 4, 20126, Milan, Italy;Department of Medicine and Surgery and Tecnomed Foundation, University of Milano-Bicocca, Via Cadore 48, 20900, Monza, Italy;Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, MI, Italy;ISBE. IT/Centre of Systems Biology, Piazza della Scienza 4, 20126, Milan, Italy;Nuclear Medicine Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy;

关键词: Metabolic rewiring;    Metabolic cancer therapy;    Metabolic signature;    Glycolysis;    Glutamine;    Combinatorial drug treatment;    Precision oncology;    Metabolic connectivity;   

DOI  :  10.1186/s40170-020-00227-4

来源: Springer

【 摘 要 】

BackgroundRewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways.MethodsWe performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity.ResultsWe show that K-Ras-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism.ConclusionsOur findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology.

【 授权许可】

CC BY