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

Cancer & Metabolism

Christian M. Metallo¹  Seth J. Parker¹  Marcella Bonanomi²  Marco Vanoni²  Federica Conte²  Giulia Fiscon²  Paola Paci²  Nicole Righi²  Federico Papa²  Anna Maria Colangelo²  Lilia Alberghina²  Rohit Bharat²  Tania Camboni³  Ingrid Cifola³  Isabella Raccagni⁴  Elisabetta Napodano⁴  Rosa Maria Moresco⁴  Daniela Gaglio⁴  Marilena Ripamonti⁴  Silvia Valtorta⁴ 

[1] Department of Bioengineering, University of California;ISBE. IT/Centre of Systems Biology;Institute for Biomedical Technologies (ITB), National Research Council (CNR);Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR);

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

DOI  :  10.1186/s40170-020-00227-4

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown