@article{fc88ab0c1657406488f143e46f6b14d1,
title = "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.",
keywords = "akt, cancer cells, growth, heat-shock-protein, heat-shock-protein-27, hsp27, metabolism, ras, resistance, targeted therapies",
author = "J. Bellier and M.J. Nokin and M. Caprasse and A. Tiamiou and A. Blomme and J.L. Scheijen and B. Koopmansch and G.M. MacKay and B. Chiavarina and B. Costanza and G. Rademaker and F. Durieux and F. Agirman and N. Maloujahmoum and P.G. Cusumano and P. Lovinfosse and H.Y. Leung and F. Lambert and V. Bours and C.G. Schalkwijk and R. Hustinx and O. Peulen and V. Castronovo and A. Bellahcene",
note = "Funding Information: J.B. is a T{\'e}l{\'e}vie PhD research fellow and A. Bellahc{\`e}ne. is a research director at the National Fund for Scientific Research (FNRS), Belgium. The authors are thankful to S. N{\"u}chtern and V. Hennequi{\`e}re for expert technical assistance. We thank Dr. K. Uchida (University of Tokyo, Japan) and Dr. D. Spiegel (Yale University, USA) for kindly providing anti-argpyrimidine antibody and MBo probe, respectively. The authors are thankful to Dr. S. Gofflot (CHU/ULi{\`e}ge Biobank) and Pr. A-F. Donneau (Department of Public Health, University of Li{\`e}ge). The authors acknowledge the scientific and technical support provided at the animal, imaging and flow cytometry, genomics, viral vectors, and immunohistology technology platforms of the GIGA-Research Institute (University of Li{\`e}ge, Belgium). This work was supported by a grant from T{\'e}l{\'e}vie-FNRS ( J.0007.19 ) awarded to A. Bellahc{\`e}ne. We thank the FNRS, University of Li{\`e}ge, and Fondation L{\'e}on Fredericq for support. A. Blomme, G.M. MacKay, and H.Y. Leung were supported by Cancer Research UK Beatson Institute core funding ( C596/A17196 ) and CRUK core group awarded to H.Y.L (A22904). Funding Information: J.B. is a T?l?vie PhD research fellow and A. Bellahc?ne. is a research director at the National Fund for Scientific Research (FNRS), Belgium. The authors are thankful to S. N?chtern and V. Hennequi?re for expert technical assistance. We thank Dr. K. Uchida (University of Tokyo, Japan) and Dr. D. Spiegel (Yale University, USA) for kindly providing anti-argpyrimidine antibody and MBo probe, respectively. The authors are thankful to Dr. S. Gofflot (CHU/ULi?ge Biobank) and Pr. A-F. Donneau (Department of Public Health, University of Li?ge). The authors acknowledge the scientific and technical support provided at the animal, imaging and flow cytometry, genomics, viral vectors, and immunohistology technology platforms of the GIGA-Research Institute (University of Li?ge, Belgium). This work was supported by a grant from T?l?vie-FNRS (J.0007.19) awarded to A. Bellahc?ne. We thank the FNRS, University of Li?ge, and Fondation L?on Fredericq for support. A. Blomme, G.M. MacKay, and H.Y. Leung were supported by Cancer Research UK Beatson Institute core funding (C596/A17196) and CRUK core group awarded to H.Y.L (A22904). J.B. V.C. and A. Bellahc?ne conceived and designed the experiments. J.B. M.-J.N. M.C. A.T. A. Blomme, J.L.S. B.K. G.M.M. B. Chiavarina, B. Costanza, G.R. F.D. F.A. and N.M. performed the experiments and acquired data. J.B. M.-J.N. M.C. A.T. A. Blomme, J.L.S. B.K. G.M.M. B. Chiavarina, B. Costanza, G.R. H.Y.L. F.D. F.L. V.B. C.G.S. O.P. V.C. and A. Bellahc?ne analyzed the data. P.L. and R.H. provided and evaluated clinical information. P.G.C. provided with essential reagents. J.B. and A. Bellahc?ne wrote the main manuscript text. All authors critically reviewed and approved the final manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = feb,
day = "4",
doi = "10.1016/j.celrep.2020.01.012",
language = "English",
volume = "30",
pages = "1400--1416.e6",
journal = "Cell Reports",
issn = "2639-1856",
publisher = "Elsevier BV",
number = "5",
}