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.
File(s)
Published version
Author(s)
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.
Date Issued
2016-09-29
Date Acceptance
2016-09-06
Citation
British Journal of Cancer, 2016, 115 (10), pp.1223-1233
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
Imperial College Trust
Identifier
PII: bjc2016313
Grant Number
N/A
Subjects
Oncology & Carcinogenesis
1112 Oncology And Carcinogenesis
Publication Status
Published