Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
Justine Bellier, Marie‐Julie Nokin, Maurine Caprasse, Assia Tiamiou, Arnaud Blomme, Jean L.J.M. Scheijen, Benjamin Koopmansch, Gillian Mackay, Barbara Chiavarina, Brunella Costanza, Gilles Rademaker, Florence Durieux, Ferman Agirman, Naïma Maloujahmoum, P. Cusumano, Pierre Lovinfosse, Hing Y. Leung, Frédéric Lambert, Vincent Bours, Casper G. Schalkwijk, Roland Hustinx, Olivier Peulen, V Castronovo, Akeila Bellahcène
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.