尼妥珠单抗
癌症研究
蛋白激酶B
PI3K/AKT/mTOR通路
MAPK/ERK通路
第1周
细胞凋亡
表皮生长因子受体
化学
药理学
医学
信号转导
细胞周期
癌症
内科学
细胞周期蛋白依赖激酶1
生物化学
作者
Dongshao Chen,Ruoxi Hong,Jiazhen Lin,Qingnan Wu,Yan Wang,Jie Chen,Jinting Li,Weimin Zhang,Qimin Zhan
出处
期刊:Carcinogenesis
[Oxford University Press]
日期:2023-06-01
卷期号:44 (6): 451-462
被引量:3
标识
DOI:10.1093/carcin/bgad038
摘要
Epidermal growth factor receptor (EGFR) is one of the most common amplified and overexpressed oncogenes in esophageal squamous cell carcinoma (ESCC), while the clinical efficacy of EGFR-targeted therapy in ESCC is dismal. Here, we evaluated the efficacy of dual blockage using monoclonal antibody against EGFR (Nimotuzumab) and an Wee1 inhibitor (AZD1775) in ESCC. We found that the mRNA and protein expression of EGFR and Wee1 were positively correlated in ESCC. Nimotuzumab-AZD1775 co-treatment inhibited tumor growth in PDX models with different drug susceptibility. Transcriptome sequencing and mass spectrometry analysis indicated that higher sensitive models showed enrichment of the PI3K/Akt or MAPK signaling pathway in Nimotuzumab-AZD1775 group compared with control group. In vitro experiments showed that the combination further inhibit PI3K/Akt and MAPK pathways compared to their monotherapy as indicated by downregulation of pAKT, pS6, pMEK, pErk and p-p38 MAPK. Furthermore, AZD1775 potentiated Nimotuzumab's antitumor effect through inducing apoptosis. Meanwhile, the bioinformatics analysis suggests the POLR2A might be candidate molecule of EGFR/Wee1 downstream. In conclusion, our work uncovers that EGFR-mAb Nimotuzumab combined with Wee1 inhibitor AZD1775 elicited potentiated anticancer activity against ESCC cell line and PDXs partially through PI3K/Akt and MAPK pathways blockade. These preclinical data raise the promising that ESCC patients may benefit from dual target EGFR and Wee1.
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