FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer.
BACKGROUND
Cetuximab, a monoclonal antibody against EGFR used for the treatment of colorectal cancer (CRC), is ineffective in many patients. The aim of this study was to identify the signalling pathways activated by cetuximab in CRC cells and define new biomarker of response.


METHODS
We used in vitro, in vivo models and clinical CRC samples to assess the role of p38 and FOXO3a in cetuximab mechanism of action.


RESULTS
We show that cetuximab activates the MAPK p38. Specifically, p38 inhibition reduced cetuximab efficacy on cell growth and cell death. At the molecular level, cetuximab activates the transcription factor FOXO3a and promotes its nuclear translocation via p38-mediated phosphorylation, leading to the upregulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation. Finally, we found that high FOXO3a and p38 expression levels are associated with better response rate and improved outcome in cetuximab-treated patients with CRC harbouring WT KRAS.


CONCLUSIONS
We identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells and define p38 as its activator in this context. Moreover, high FOXO3a and p38 expression could predict the response to cetuximab in patients with CRC harbouring WT KRAS.
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
L
L
Marzi
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
E
E
Combes
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
N
N
Vié
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
A
A
Ayrolles-Torro
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
D
D
Tosi
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
D
D
Desigaud
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
E
E
Perez-Gracia
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
C
C
Larbouret
Department of Medical Oncology, Hospital del Mar, Barcelona 08003, Spain.
C
C
Montagut
Department of Medical Oncology, Hospital del Mar, Barcelona 08003, Spain.
M
M
Iglesias
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
M
M
Jarlier
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
V
V
Denis
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
L K
LK
Linares
Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
E W-F
EW
Lam
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
P
P
Martineau
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
M
M
Del Rio
IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, F-34298, France.|INSERM, U1194, Montpellier F-34298, France.|Université Montpellier, Montpellier F-34298, France.|Institut régional du Cancer Montpellier, Montpellier F-34298, France.
C
C
Gongora
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D018938:Caco-2 Cells; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000068818:Cetuximab / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; D000068818:Cetuximab
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