Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab.

Cell reports (2020-02-06)
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
ABSTRAKT

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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