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Published on: September 30, 2016
Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
Justine Bellier1, Marie-Julie Nokin1, Maurine Caprasse1
1Metastasis Research Laboratory, GIGA-Cancer, University of Liège, Liège, Belgium.
Abstract:
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.
Insights
Methylglyoxal (MGO), a glycolysis byproduct, causes resistance to cetuximab in colorectal cancer (CRC) by activating AKT. MGO scavengers resensitize tumors to this EGFR-targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Metabolism
Background:
- Cetuximab (anti-EGFR) therapy is crucial for colorectal cancer (CRC), but response rates are limited, especially in KRAS-mutant tumors.
- Patient selection for cetuximab remains challenging due to variable response rates even in wild-type KRAS.
- Methylglyoxal (MGO), a glycolysis byproduct, was previously identified as a tumor promoter.
Purpose of the Study:
- To investigate the role of methylglyoxal (MGO) in cetuximab resistance in colorectal cancer (CRC).
- To explore the molecular mechanisms linking MGO, AKT activation, and resistance to EGFR-targeted therapy.
Main Methods:
- Comparative analysis of isogenic wild-type KRAS and mutant KRAS CRC cells under MGO stress.
- Investigation of AKT activation pathways (PI3K/mTORC2, Hsp27) induced by MGO.
- In vivo studies using MGO scavengers to assess effects on AKT and cetuximab sensitivity.
Main Results:
- Mutant KRAS CRC cells exhibit AKT-dependent survival under MGO stress compared to wild-type KRAS cells.
- MGO induces AKT activation via PI3K/mTORC2 and Hsp27 regulation.
- MGO stress confers cetuximab resistance in wild-type KRAS CRC cells, which is reversed by MGO scavengers that inhibit AKT.
Conclusions:
- Methylglyoxal (MGO) links metabolic stress to AKT activation, driving resistance to EGFR-targeted therapy in colorectal cancer.
- MGO is identified as a potential therapeutic target to overcome cetuximab resistance in CRC patients.
- Targeting MGO may improve patient outcomes for EGFR-targeted therapies in colorectal cancer.
