Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
Open accessAbstract
The use of cetuximab anti-epidermal growth factor receptor (anti-EGFR) antibodies has opened the era of targeted and personalized therapy in colorectal cancer (CRC). Poor response rates have been unequivocally shown in mutant KRAS and are even observed in a majority of wild-type KRAS tumors. Therefore, patient selection based on mutational profiling remains problematic. We previously identified methylglyoxal (MGO), a by-product of glycolysis, as a metabolite promoting tumor growth and metastasis. Mutant KRAS cells under MGO stress show AKT-dependent survival when compared with wild-type KRAS isogenic CRC cells. MGO induces AKT activation through phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin 2 (mTORC2) and Hsp27 regulation. Importantly, the sole induction of MGO stress in sensitive wild-type KRAS cells renders them resistant to cetuximab. MGO scavengers inhibit AKT and resensitize KRAS-mutated CRC cells to cetuximab in vivo. This study establishes a link between MGO and AKT activation and pinpoints this oncometabolite as a potential target to tackle EGFR-targeted therapy resistance in CRC.
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Glycolytic KRAS-mutant cells produce increased amounts of methylglyoxal.
“Moreover, glycolytic KRAS-mutant cells produce increased amounts of potentially toxic byproducts of glycolysis such as methylglyoxal40.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [40]
Methylglyoxal-mediated stress is involved in cancer progression and activates AKT signaling, suggesting that methylglyoxal scavengers may be more effective with AKT inhibitors in KRAS-mutant colorectal cancer cells.
“Methylglyoxal-mediated stress was shown to be involved in cancer progression41 and to be a potent activator of AKT signaling, suggesting that utilizing methylglyoxal scavengers in KRAS mutant colorectal cancer cells might be more effective when combined with AKT inhibitors40.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [40]
Small chemical compounds such as KY7749 and methylglyoxal scavengers resensitize KRAS-mutated colorectal cancer cells to cetuximab in vivo.
“In addition, small chemical compounds such as KY7749 and methylglyoxal scavengers resensitize KRAS-mutated CRC cells to cetuximab in vivo [48, 89].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [48]
The methylglyoxal scavenger carnosine was confirmed to resensitize KRAS-mutated colorectal tumours to cetuximab in vivo.
“The methylglyoxal scavenger carnosine was confirmed to resensitize KRAS-mutated colorectal tumours to cetuximab in vivo [48].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [48]
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Research works printed but not linked: 1
- Rodriguez-Viciana, P., Warne, P.H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M.J., Waterfield, M.D., and Downward, J. (1994). Phosphatidylinositol-3OH kinase as a direct target of Ras. Nature 370 , 527-532. http://refhub.elsevier.com/S2211-1247(2030021-8/sref62)
Cited by
Sorted by citations
The metabolic landscape of RAS-driven cancers from biology to therapy
Mukhopadhyay, S., Vander Heiden, M. G., & McCormick, F. (2021) · Nature Cancer · doi:10.1038/s43018-021-00184-x · Cited by 315 · see citing works
Zhou, J., Ji, Q., & Li, Q. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02130-2 · Cited by 246 · see citing works
- Authors
- Bellier, J., Nokin, M.-J., Caprasse, M., Tiamiou, A., Blomme, A., Scheijen, J. L., Koopmansch, B., MacKay, G. M., Chiavarina, B., Costanza, B., Rademaker, G., Durieux, F., Agirman, F., Maloujahmoum, N., Cusumano, P. G., Lovinfosse, P., Leung, H. Y., Lambert, F., Bours, V., Schalkwijk, C. G., Hustinx, R., Peulen, O., Castronovo, V., & Bellahcène, A.
- Affiliations
- University of Liège (BE)
- Cancer Research UK Scotland Institute (GB)
- Maastricht University (NL)
- Centre Hospitalier Universitaire de Liège (BE)
- Corresponding author
- Bellahcène, Akeila
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 30
- Issue
- 5
- Pages
- 1400-1416.e6
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W3005078956
- Cited by
- 38
- References
- 82
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 5 · 2021: 12 · 2020: 1
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Update notices
- erratum (2026-07-28)
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, cc-by)
- Funders
- Beatson Institute for Cancer Research (C596/A17196)
- Fonds De La Recherche Scientifique - FNRS
- Université de Liège
- Fonds Léon Fredericq
- Cancer Research UK (A22904)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- methylglyoxal, cetuximab, KRAS mutation, colorectal cancer, anti-EGFR therapy resistance, Akt activation, HSP27, oncometabolites, drug re-sensitization
- MeSH terms
- Cetuximab, Mechanistic Target of Rapamycin Complex 2, Adult, Aged, Aged, 80 and over, Animals, Carnosine, Clone Cells, Enzyme Activation, Glycolysis, Glycosylation, Humans, Male, Middle Aged, Mutation, Pyruvaldehyde, Stress, Physiological, Colorectal Neoplasms, Free Radical Scavengers, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Phosphatidylinositol 3-Kinases, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-akt, HSP27 Heat-Shock Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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