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

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

Varshavi, Dorna, Varshavi, Dorsa, Veselkov, Kirill, McCarthy, Nicola, Keun, Hector C. and Everett, Jeremy R. ORCID: 0000-0003-1550-4482 (2020) Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines. Metabolomics, 16 (4):51. ISSN 1573-3882 (Print), 1573-3890 (Online) (doi:https://doi.org/10.1007/s11306-020-01674-2)

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Abstract

Introduction:
KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) 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.

Item Type: Article
Additional Information: Publishing under Springer Open Choice Open Access with Creative Commons CC-BY.
Uncontrolled Keywords: KRAS, mutations, SW48, cells, colorectal cancer, metabonomics, metabolomics, metabolic profiling, NMR
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Faculty / Department / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > School of Science (SCI)
Last Modified: 06 May 2020 10:05
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
Selected for GREAT 2019: None
Selected for REF2021: REF 5
URI: http://gala.gre.ac.uk/id/eprint/24953

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