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Varshavi D, Varshavi D, McCarthy N, et al. Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines. Metabolomics. 2021;17(12):104doi: 10.1007/s11306-021-01852-w.
Varshavi, D., Varshavi, D., McCarthy, N., Veselkov, K., Keun, H. C., & Everett, J. R. (2021). Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines. Metabolomics : Official journal of the Metabolomic Society, 17(12), 104. https://doi.org/10.1007/s11306-021-01852-w
Varshavi, Dorna, et al. "Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines." Metabolomics : Official journal of the Metabolomic Society vol. 17,12 (2021): 104. doi: https://doi.org/10.1007/s11306-021-01852-w
Varshavi D, Varshavi D, McCarthy N, Veselkov K, Keun HC, Everett JR. Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines. Metabolomics. 2021 Nov 25;17(12):104. doi: 10.1007/s11306-021-01852-w. PMID: 34822010; PMCID: PMC8616861.
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Metabolomics. 2021 Nov 25;17(12):104. doi: 10.1007/s11306-021-01852-w.

Metabonomics study of the effects of single copy mutant KRAS in the presence or absence of WT allele using human HCT116 isogenic cell lines.

Metabolomics : Official journal of the Metabolomic Society

Dorna Varshavi, Dorsa Varshavi, Nicola McCarthy, Kirill Veselkov, Hector C Keun, Jeremy R Everett

Affiliations

  1. Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, ME4 4TB, Kent, UK.
  2. Department of Biological Sciences, University of Alberta, 116 Street & 85 Ave, Edmonton, AB, T6G 2R3, Canada.
  3. Horizon Discovery Ltd., Cambridge Research Park, 8100 Beach Dr, Waterbeach, Cambridge, CB25 9TL, UK.
  4. Milner Therapeutics Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Puddicombe Way, Cambridge, CB2 0AW, UK.
  5. Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, SW7 2AZ, UK.
  6. Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 ONN, UK.
  7. Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, ME4 4TB, Kent, UK. [email protected].

PMID: 34822010 PMCID: PMC8616861 DOI: 10.1007/s11306-021-01852-w

Abstract

INTRODUCTION: KRAS was one of the earliest human oncogenes to be described and is one of the most commonly mutated genes in different human cancers, including colorectal cancer. Despite KRAS mutants being known driver mutations, KRAS has proved difficult to target therapeutically, necessitating a comprehensive understanding of the molecular mechanisms underlying KRAS-driven cellular transformation.

OBJECTIVES: To investigate the metabolic signatures associated with single copy mutant KRAS in isogenic human colorectal cancer cells and to determine what metabolic pathways are affected.

METHODS: Using NMR-based metabonomics, we compared wildtype (WT)-KRAS and mutant KRAS effects on cancer cell metabolism using metabolic profiling of the parental KRAS

RESULTS: Mutation in the KRAS oncogene leads to a general metabolic remodelling to sustain growth and counter stress, including alterations in the metabolism of amino acids and enhanced glutathione biosynthesis. Additionally, we show that KRAS

CONCLUSIONS: Our study showed the effect of a single point mutation in one KRAS allele and KRAS allele loss in an isogenic genetic background, hence avoiding confounding genetic factors. Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS.

© 2021. The Author(s).

Keywords: Cells; Colorectal cancer; HCT116; KRAS; Metabolic profiling; Metabolomics; Metabonomics; Mutations; NMR

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