Abstract
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.
Highlights
Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth
Human HCT116 colon cancer cells are more respiratory than A549 lung cancer cells Oncogenic K-Ras may alter glucose and glutamine metabolism to sustain enhanced cell proliferation [13, 26]
Concurrent drug perturbation of glucose and glutamine utilization pathways severely reduces the growth of A549 and HCT116 xenografts and cell lines
Summary
Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. A metabolic rewiring in which glucose is converted to lactate, while glutamine-derived α-ketoglutarate (Akg) enters the tricarboxylic acid cycle (TCA)—undergoing partial reductive carboxylation to citrate [1]— characterize a large number of cancer cells. This basic scheme may be modified by the presence in the cellular environment (both in vitro and in vivo) of lactate and/or amino acids such as proline, arginine, and asparagine, thereby generating a variety of complex and flexible metabolic pathways sustaining the enhanced and unrestricted growth of cancer cells [2,3,4,5]. This new approach will open the way to systems metabolomics as a new, robust, customizable tool for cancer precision medicine [11]
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