FOXO1 links KRAS G12D and G12V alleles to glutamine and nitrogen metabolism in colorectal cancer
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.
Authors
- Shamith Samarajiwa (ORCID: https://orcid.org/0000-0003-1046-0601)
- Christian Frezza (ORCID: https://orcid.org/0000-0002-3293-7397)
- Ming Yang (ORCID: https://orcid.org/0000-0002-7735-7804)
- Annie Howitt (ORCID: https://orcid.org/0000-0003-0388-0990)
- Simon J. Cook (ORCID: https://orcid.org/0000-0001-9087-1616)
- Marco Sciacovelli (ORCID: https://orcid.org/0000-0003-2958-4292)
- Suzan Ber (ORCID: https://orcid.org/0000-0003-4219-6032)
- Alessandro Esposito (ORCID: https://orcid.org/0000-0002-5051-091X)
- Ashok R. Venkitaraman (ORCID: https://orcid.org/0000-0002-6876-2672)
- Efterpi Nikitopoulou (ORCID: https://orcid.org/0000-0003-2517-5555)
- Khushali Patel (ORCID: https://orcid.org/0000-0003-4991-4527)
Institutions
- Babraham Institute (GB)
- University of Liverpool (GB)
- National University of Singapore (SG)
- University of Cologne (DE)
- University of Cambridge (GB)
- MRC Cancer Unit (GB)
- National University Cancer Institute, Singapore (SG)
- National Cancer Centre Singapore (SG)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Cologne (DE)
- Brunel University of London (GB)
- Institute of Molecular and Cell Biology (SG)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1038/s44319-025-00641-z
- Citations
- 1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94