Institute of Biomedicine and Medicity Research Laboratories, University of Turku, Turku, Finland.
Turku Doctoral Programme of Molecular Medicine, Turku, Finland.
Sci Rep. 2018 Nov 8;8(1):16579. doi: 10.1038/s41598-018-34938-y.
Therapeutic protocols including EGFR antibodies in the context of oxaliplatin-based regimens have variable clinical effect in colorectal cancer. Here, we tested the effect of the EGFR antibody cetuximab in different sequential combinations with oxaliplatin on the growth of colorectal cancer cells in vitro and in vivo. Cetuximab reduced the efficacy of oxaliplatin when administered before oxaliplatin but provided additive effect when administered after oxaliplatin regardless of the KRAS or BRAF mutation status of the cells. Systemic gene expression and protein phosphorylation screens revealed alternatively activated pathways regulating apoptosis, cell cycle and DNA damage response. Functional assays indicated that cetuximab-induced arrest of the cells into the G1 phase of the cell cycle was associated with reduced responsiveness of the cells to subsequent treatment with oxaliplatin. In contrast, oxaliplatin-enhanced responsiveness to subsequent treatment with cetuximab was associated with increased apoptosis, inhibition of STAT3 activity and increased EGFR down-regulation. This preclinical study indicates that optimizing the sequence of administration may enhance the antitumor effect of combination therapy with EGFR antibodies and oxaliplatin.
在基于奥沙利铂的方案中，包括 EGFR 抗体在内的治疗方案在结直肠癌中具有不同的临床效果。在这里，我们测试了 EGFR 抗体西妥昔单抗与奥沙利铂以不同顺序组合对体外和体内结直肠癌细胞生长的影响。当西妥昔单抗在奥沙利铂之前给药时，它降低了奥沙利铂的疗效，但无论细胞的 KRAS 或 BRAF 突变状态如何，当它在奥沙利铂之后给药时，都具有相加效应。系统基因表达和蛋白质磷酸化筛选揭示了调节细胞凋亡、细胞周期和 DNA 损伤反应的替代激活途径。功能测定表明，西妥昔单抗诱导细胞进入细胞周期的 G1 期停滞与细胞对随后奥沙利铂治疗的反应性降低有关。相比之下，奥沙利铂增强了随后对西妥昔单抗治疗的反应性，与增加的细胞凋亡、STAT3 活性抑制和 EGFR 下调增加有关。这项临床前研究表明，优化给药顺序可能会增强 EGFR 抗体和奥沙利铂联合治疗的抗肿瘤作用。
