Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab.
Cell Rep
; 30(5): 1400-1416.e6, 2020 02 04.
Article
em En
| MEDLINE
| ID: mdl-32023458
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aldeído Pirúvico
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Neoplasias Colorretais
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Sequestradores de Radicais Livres
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Proteínas Proto-Oncogênicas p21(ras)
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Cetuximab
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Animals
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2020
Tipo de documento:
Article