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Bellier, Justine; Nokin, Marie-Julie; Caprasse, Maurine; Tiamiou, Assia; Blomme, Arnaud; Scheijen, Jean L.; Koopmansch, Benjamin; MacKay, Gillian M.; Chiavarina, Barbara; Costanza, Brunella; Rademaker, Gilles; Durieux, Florence; Agirman, Ferman; Maloujahmoum, Naïma; Cusumano, Pino G.; Lovinfosse, Pierre; Leung, Hing Y.; Lambert, Frédéric; Bours, Vincent; Schalkwijk, Casper G.; Hustinx, Roland; Peulen, Olivier; Castronovo, Vincent; Bellahcène, Akeila
Cell reports, 02/2020, Volume: 30, Issue: 5Journal Article, Web Resource
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. Display omitted •Glycolytic mutant KRAS display higher MGO stress than wild-type CRC cells•MGO stress is a potent inducer of AKT signaling in CRC cells•MGO stress induces resistance to anti-EGFR therapy in a wild-type KRAS setting•Carnosine, an MGO scavenger, sensitizes mutant KRAS CRC tumors to anti-EGFR therapy 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.
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