Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab

J. Bellier, M.J. Nokin, M. Caprasse, A. Tiamiou, A. Blomme, J.L. Scheijen, B. Koopmansch, G.M. MacKay, B. Chiavarina, B. Costanza, G. Rademaker, F. Durieux, F. Agirman, N. Maloujahmoum, P.G. Cusumano, P. Lovinfosse, H.Y. Leung, F. Lambert, V. Bours, C.G. SchalkwijkR. Hustinx, O. Peulen, V. Castronovo, A. Bellahcene*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Web of Science)

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.
Original languageEnglish
Pages (from-to)1400-+
Number of pages23
JournalCell Reports
Volume30
Issue number5
DOIs
Publication statusPublished - 4 Feb 2020

Keywords

  • akt
  • cancer cells
  • growth
  • heat-shock-protein
  • heat-shock-protein-27
  • hsp27
  • metabolism
  • ras
  • resistance
  • targeted therapies

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