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Kirsten Rat Sarcoma Viral Oncogene Homolog ( KRAS ) mutations occur in approximately one-third of colorectal (CRC) tumours and have been associated with poor prognosis and resistance to some therapeutics. In addition to the well-documented pro-tumorigenic role of mutant Ras alleles, there is some evidence suggesting that not all  KRAS  mutations are equal and the position and type of amino acid substitutions regulate biochemical activity and transforming capacity of  KRAS  mutations.    Objectives  To investigate the metabolic signatures associated with different  KRAS  mutations in codons 12, 13, 61 and 146 and to determine what metabolic pathways are affected by different  KRAS  mutations.    Methods  We applied an NMR-based metabonomics approach to compare the metabolic profiles of the intracellular extracts and the extracellular media from isogenic human SW48 CRC cell lines with different  KRAS  mutations in codons 12 (G12D, G12A, G12C, G12S, G12R, G12V), 13 (G13D), 61 ( Q61H ) and 146 ( A146T ) with their wild-type counterpart. We used false discovery rate (FDR)-corrected analysis of variance (ANOVA) to determine metabolites that were statistically significantly different in concentration between the different mutants.    Results  CRC cells carrying distinct  KRAS  mutations exhibited differential metabolic remodelling, including differences in glycolysis, glutamine utilization and in amino acid, nucleotide and hexosamine metabolism.    Conclusions  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.Electronic supplementary material  The online version of this article (10.1007/s11306-020-01674-2) contains supplementary material, which is available to authorized users.

metabolomics

Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines