ReferenceID 5797
Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
Cell Rep
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 m
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Record Fields
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- Reference Id
- 5797
- Evidence Id
- 22387
- Core Evidence Id
- 22387
- Source Reference Id
- 4835
- Herb2 Reference Id
- HBREF005632
- Subject Paper Key
- HBIN035246_32023458
- Pubmed Id
- 32023458
- Doi
- 10.1016/j.celrep.2020.01.012
- Paper Title
- Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
- Paper 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.
- Journal
- Cell Rep
- Publish Year
- 2020
- Experiment Subject
- patient; kras cells; kras-mutated crc cells; wild-type kras cells; wild-type kras isogenic crc cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Kras Tumors; Tumor; Colorectal Cancer
- Paper Title Cn
- Paper Title En
- Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
- Bilingual Status
- semi_complete