Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab.

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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 30 Issue 5 Pg. 1400-1416.e6 (02 04 2020) ISSN: 2211-1247 [Electronic] United States
• PMID: 32023458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Free Radical Scavengers
• HSP27 Heat-Shock Proteins
• KRAS protein, human
• Pyruvaldehyde
• Carnosine
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins p21(ras)
• Cetuximab

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Carnosine (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cetuximab (pharmacology, therapeutic use)
• Clone Cells
• Colorectal Neoplasms (drug therapy)
• Enzyme Activation (drug effects)
• Free Radical Scavengers (pharmacology)
• Glycolysis (drug effects)
• Glycosylation (drug effects)
• HSP27 Heat-Shock Proteins (metabolism)
• Humans
• Male
• Mechanistic Target of Rapamycin Complex 2 (metabolism)
• Mice, Inbred NOD
• Mice, SCID
• Middle Aged
• Mutation (genetics)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Pyruvaldehyde (pharmacology)
• Stress, Physiological (drug effects)