| Title: |
FOXO1 links KRAS G12D and G12V alleles to glutamine and nitrogen metabolism in colorectal cancer |
| Authors: |
Ber, S; Yang, M; Sciacovelli, M; Samarajiwa, S; Patel, K; Nikitopoulou, E; Howitt, A; Cook, SJ; Venkitaraman, AR; Frezza, C; Esposito, A |
| Publisher Information: |
Springer Nature on behalf of EMBO Press |
| Publication Year: |
2025 |
| Collection: |
Brunel University London: Brunel University Research Archive (BURA) |
| Subject Terms: |
FOXO signalling; KRAS mutation; glutamine metabolism; colorectal cancer; glutamine synthase |
| Description: |
Data availability: The RNA-seq results and analysis software is available in the source data files and described in the Appendix. Raw RNA sequencing data is available at the Gene Expression Omnibus (Barrett et al, 2012) with accession number GSE306286 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE306286). The matabolomics results are available in source data files. Raw LC-MS data is available at Metabolomics Workbench (Sud et al, 2016) with accession number ST004144 (https://doi.org/10.21228/M8NZ6Q). The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_1038-S44319-025-00641-z . ; Supplementary Material is available online at: https://www.embopress.org/doi/full/10.1038/s44319-025-00641-z#supplementary-materials . ; Mutations in KRAS, particularly at codon 12, are frequent in adenocarcinomas of the colon, lungs and pancreas, driving carcinogenesis by altering cell signalling and reprogramming metabolism. However, the specific mechanisms by which different KRAS G12 alleles initiate distinctive patterns of metabolic reprogramming are unclear. Using isogenic panels of colorectal cell lines harbouring the G12A, G12C, G12D and G12V heterozygous mutations and employing transcriptomics, metabolomics, and extensive biochemical validation, we characterise distinctive features of each allele. We demonstrate that cells harbouring the common G12D and G12V oncogenic mutations significantly alter glutamine metabolism and nitrogen recycling through FOXO1-mediated regulation compared to parental lines. Moreover, with a combination of small molecule inhibitors targeting glutamine and glutamate metabolism, we also identify a common vulnerability that eliminates mutant cells selectively. These results highlight a previously unreported mutant-specific effect of KRAS alleles on metabolism and signalling that could be potentially harnessed for cancer therapy. ; Cancer Research UK (CRUK): C54674/A27487, C51061/A27453; Cambridge University | Cancer Research UK Cambridge Institute, ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
1 - 21; Electronic |
| Language: |
English |
| Relation: |
EMBO Reports; https://bura.brunel.ac.uk/handle/2438/32390 |
| DOI: |
10.1038/s44319-025-00641-z |
| Availability: |
https://bura.brunel.ac.uk/handle/2438/32390; https://doi.org/10.1038/s44319-025-00641-z |
| Rights: |
Creative Commons Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ ; https://creativecommons.org/licenses/by/4.0/legalcode.en ; The Author(s) |
| Accession Number: |
edsbas.BAB0BB30 |
| Database: |
BASE |