Article (Scientific journals)
Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
Bellier, Justine; Nokin, Marie-Julie; Caprasse, Maurine et al.
2020In Cell Reports, 30 (5), p. 1400-1416.e6
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Keywords :
AKT signaling; EGFR-targeted therapy; Hsp27; KRAS mutation; aminoguanidine; carnosine; cetuximab; colorectal cancer; methylglyoxal
Abstract :
[en] 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.
Research center :
Giga-Cancer - ULiège
GIGA‐R - Giga‐Research - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Gastroenterology & hepatology
Oncology
Author, co-author :
Bellier, Justine 
Nokin, Marie-Julie  
Caprasse, Maurine 
Tiamiou, Assia ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Blomme, Arnaud  ;  Cancer Research UK Beatson Institute
Scheijen, Jean L.
KOOPMANSCH, Benjamin 
MacKay, Gillian M.
Chiavarina, Barbara 
Costanza, Brunella 
Rademaker, Gilles  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire
Cusumano, Pino G.
Leung, Hing Y.
Bours, Vincent ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique humaine
Schalkwijk, Casper G.
Hustinx, Roland  ;  Université de Liège - ULiège > Département des sciences cliniques > Médecine nucléaire
Peulen, Olivier  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Bellahcene, Akeila  ;  Université de Liège - ULiège > Cancer-Metastases Research Laboratory
More authors (14 more) Less
Language :
English
Title :
Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab
Publication date :
04 February 2020
Journal title :
Cell Reports
eISSN :
2211-1247
Publisher :
Elsevier, Amsterdam, Netherlands
Volume :
30
Issue :
5
Pages :
1400-1416.e6
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
Role of methylglyoxal stress in the resistance of KRAS mutated human colon cancer to targeted therapy
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Commentary :
Copyright (c) 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Available on ORBi :
since 27 February 2020

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