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.
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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DOI：
10.1038/bjc.2016.313
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发表时间：
2016-11-08
影响因子：
8.8
通讯作者：
Gongora, C.
中科院分区：
文献类型：
--
作者：
Marzi, L.;Combes, E.;Vie, N.;Ayrolles-Torro, A.;Tosi, D.;Desigaud, D.;Perez-Gracia, E.;Larbouret, C.;Montagut, C.;Iglesias, M.;Jarlier, M.;Denis, V.;Linares, L. K.;Lam, E. W-F;Martineau, P.;Del Rio, M.;Gongora, C.
西妥昔单抗（Cetuximab）是一种用于治疗结直肠癌（CRC）的抗EGFR单克隆抗体，对许多患者无效。本研究的目的是确定西妥昔单抗在结直肠癌细胞中激活的信号通路，并定义新的生物标志物。我们通过体外、体内模型和临床CRC样本来评估p38和FOXO3a在西妥昔单抗作用机制中的作用。我们发现西妥昔单抗激活MAPK p38。具体来说，p38抑制降低了西妥昔单抗对细胞生长和细胞死亡的作用。在分子水平上，西妥昔单抗通过p38介导的磷酸化激活转录因子FOXO3a，促进其核易位，导致其靶基因p27和BIM上调，进而诱导细胞凋亡，抑制细胞增殖。最后，我们发现，在西妥昔单抗治疗的携带WT KRAS的CRC患者中，FOXO3a和p38的高表达水平与更好的缓解率和改善的预后相关。我们确定FOXO3a是西妥昔单抗在CRC细胞中作用机制的关键介质，并在此背景下确定p38为其激活剂。此外，FOXO3a和p38的高表达可以预测携带WT KRAS的CRC患者对西妥昔单抗的反应。
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. We used in vitro, in vivo models and clinical CRC samples to assess the role of p38 and FOXO3a in cetuximab mechanism of action. 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. 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.
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影响因子：
5.1
作者：
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