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.

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Title: 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.
Authors: Marzi, L
Combes, E
Vié, N
Ayrolles-Torro, A
Tosi, D
Desigaud, D
Perez-Gracia, E
Larbouret, C
Montagut, C
Iglesias, M
Jarlier, M
Denis, V
Linares, LK
Lam, EW
Martineau, P
Del Rio, M
Gongora, C
Item Type: Journal Article
Abstract: 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.British Journal of Cancer advance online publication, 29 September 2016; doi:10.1038/bjc.2016.313 www.bjcancer.com.
Issue Date: 29-Sep-2016
Date of Acceptance: 6-Sep-2016
URI: http://hdl.handle.net/10044/1/41558
DOI: https://dx.doi.org/10.1038/bjc.2016.313
ISSN: 1532-1827
Publisher: Cancer Research UK
Start Page: 1223
End Page: 1233
Journal / Book Title: British Journal of Cancer
Volume: 115
Issue: 10
Copyright Statement: © 2016 Cancer Research UK. All rights reserved.
Sponsor/Funder: Imperial College Trust
Funder's Grant Number: N/A
Keywords: Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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