Résumé
Cetuximab is a monoclonal antibody against EGFR and is associated with 5-FU and irinotecan for the treatment of patients with colorectal cancer harboring wild type KRAS. However, cetuximab is ineffective in patients with constitutively active mutated KRAS and also in half of the patients with wild type KRAS. As cetuximab downstream cellular targets are not fully characterized, the aim of this study was to identify the signaling pathways activated by cetuximab in CRC cells. Our results show that in addition to inhibiting ERK and AKT, cetuximab also activates the mitogen-activated protein kinase (MAPK) p38. We have showed that 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. FOXO3a phosphorylation and activation by p38 led to the up-regulation of its target genes p27 and BIM and the subsequent induction of apoptosis and inhibition of cell proliferation. Finally, FOXO3a silencing reduced cetuximab cytotoxicity, further confirming FOXO3a role in cetuximab effect. Collectively, our results identify FOXO3a as a key mediator of cetuximab mechanism of action in CRC cells KRAS WT and define p38 as its main activator in this context.
Citation Format: Laetitia Marzi, Eve Combes, Nadia VIE, Diego Tosi, Adeline Ayrolles-Torro, Christel Larbouret, Vincent Denis, Laetitia K. Linares, Clara Montagut, Mar Iglesias, Pierre Martineau, Eric W-F Lam, Maguy Del Rio, Céline Gongora. Cetuximab activates Foxo3a via the MAPK p38 to induce apoptosis and reduce cell proliferation in colorectal cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B16.