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

Abstract

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.

• Authors: Daniela Gaglio, Marcella Bonanomi, Silvia Valtorta, Rohit Bharat, Marilena Ripamonti, Federica Conte, Giulia Fiscon, Nicole Righi, Elisabetta Napodano, Federico Papa, Isabella Raccagni, Seth J Parker, Ingrid Cifola, Tania Camboni, Paola Paci, Anna Maria Colangelo, Marco Vanoni, Christian M Metallo, Rosa Maria Moresco, Lilia Alberghina
• Journal: Cancer & metabolism (Cancer Metab) Vol. 8 Pg. 22 ( 2020) ISSN: 2049-3002 [Print] England
• PMID: 33005401 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2020.