Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity pr
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RESEARCH
Open Access
Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling Daniela Gaglio1,2* , Marcella Bonanomi2,3, Silvia Valtorta1,2,4, Rohit Bharat2,3, Marilena Ripamonti1,2, Federica Conte2,5, Giulia Fiscon2,5, Nicole Righi2,3, Elisabetta Napodano1,2, Federico Papa2,5, Isabella Raccagni1,2,6, Seth J. Parker7,8, Ingrid Cifola9, Tania Camboni9, Paola Paci2,5,10, Anna Maria Colangelo2,3, Marco Vanoni2,3, Christian M. Metallo7,8, Rosa Maria Moresco1,2,4 and Lilia Alberghina2,3 Abstract: Background: Rewiring 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. Methods: We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity. Results: We 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. Conclusions: Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology. Keywords: Metabolic rewiring, Metabolic cancer therapy, Metabolic signature, Glycolysis, Glutamine, Combinatorial drug treatment, Precision oncology, Metabolic connectivity
* Correspondence: [email protected] 1 Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Segrate, MI, Italy 2 ISBE. IT/Centre of Systems Biology, Piazza della Scienza 4, 20126 Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright hol
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