Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
| Autor: | Justine Bellier, Marie-Julie Nokin, Maurine Caprasse, Assia Tiamiou, Arnaud Blomme, Jean L. Scheijen, Benjamin Koopmansch, Gillian M. MacKay, Barbara Chiavarina, Brunella Costanza, Gilles Rademaker, Florence Durieux, Ferman Agirman, Naïma Maloujahmoum, Pino G. Cusumano, Pierre Lovinfosse, Hing Y. Leung, Frédéric Lambert, Vincent Bours, Casper G. Schalkwijk, Roland Hustinx, Olivier Peulen, Vincent Castronovo, Akeila Bellahcène |
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| Přispěvatelé: | MUMC+: MA Alg Onderzoek Interne Geneeskunde (9), Interne Geneeskunde, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male Glycosylation akt growth HSP27 Heat-Shock Proteins heat-shock-protein Cetuximab Mechanistic Target of Rapamycin Complex 2 Mice SCID resistance Proto-Oncogene Proteins p21(ras) Phosphatidylinositol 3-Kinases Mice Inbred NOD Stress Physiological Cell Line Tumor Animals Humans neoplasms lcsh:QH301-705.5 ras Aged Cell Proliferation Aged 80 and over Carnosine Free Radical Scavengers Middle Aged Pyruvaldehyde digestive system diseases heat-shock-protein-27 targeted therapies Clone Cells Enzyme Activation lcsh:Biology (General) Mutation cancer cells hsp27 Colorectal Neoplasms metabolism Glycolysis Proto-Oncogene Proteins c-akt |
| Zdroj: | Cell Reports, 30(5), 1400-1416.e6. Cell Press Cell Reports, Vol 30, Iss 5, Pp 1400-1416.e6 (2020) |
| ISSN: | 2211-1247 |
| Popis: | Summary: 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. : Bellier et al. demonstrate that MGO stress is a constant feature of KRAS-mutated CRC tumors. MGO induces a key survival pathway implicated in resistance to EGFR-targeted therapy in CRC. The scavenging of this oncometabolite could be beneficial in the treatment of both wild-type and mutant KRAS CRC tumors. Keywords: methylglyoxal, colorectal cancer, KRAS mutation, EGFR-targeted therapy, Hsp27, carnosine, aminoguanidine, cetuximab, AKT signaling |
| Databáze: | OpenAIRE |
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