Lin Chengzhong, Lu Wei, Ren Zhenhu, Tang Yu, Zhang Chunye, Yang Rong, Chen Yiming, Cao Wei, Wang Lizhen, Wang Xu, Ji Tong
Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai 200011, China.
Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Cancer Lett. 2016 Jul 10;377(1):1-10. doi: 10.1016/j.canlet.2016.04.023. Epub 2016 Apr 18.
Co-activation of EGFR by alternative receptor tyrosine kinases (RTKs) might mediate resistance to EGFR inhibition in head and neck squamous cell carcinoma (HNSCC). Here we found a novel mechanism to improve the efficacy of EGFR inhibitor erlotinib on HNSCC.
Immunohistochemistry, western blot, cell migration and invasion assays, cell proliferation, cell cycle analysis and in vivo serial transplantation assays were used to evaluate the role of RET on HNSCC cells.
The elevated levels of a rearranged during transfection (RET) are observed in HNSCC and that high levels of RET correlate with increased tumor size, advanced tumor stage and decreased overall survival rate. The HNSCC cell proliferation and invasion were inhibited by RET knockdown in vitro and in vivo. The inhibition of RET expression markedly reduced EGFR phosphorylation and downstream EGFR signaling. The inhibition of RET signaling significantly increased the sensitivity of HNSCC cells to the EGFR inhibitor erlotinib in both in vitro and in vivo models.
Our results offer a preclinical proof-of-concept supporting a role for RET signaling inhibition in a targeted therapeutic approach to improve the efficacy of EGFR inhibition in HNSCC.
在头颈部鳞状细胞癌（HNSCC）中，替代受体酪氨酸激酶（RTK）对表皮生长因子受体（EGFR）的共激活可能介导对EGFR抑制的耐药性。在此，我们发现了一种提高EGFR抑制剂厄洛替尼对HNSCC疗效的新机制。
采用免疫组织化学、蛋白质免疫印迹法、细胞迁移和侵袭试验、细胞增殖、细胞周期分析及体内连续移植试验来评估RET在HNSCC细胞中的作用。
在HNSCC中观察到转染期间重排（RET）水平升高，且RET高水平与肿瘤大小增加、肿瘤分期进展及总生存率降低相关。在体外和体内，RET基因敲低均抑制了HNSCC细胞的增殖和侵袭。抑制RET表达显著降低了EGFR磷酸化及下游EGFR信号传导。在体外和体内模型中，抑制RET信号传导均显著提高了HNSCC细胞对EGFR抑制剂厄洛替尼的敏感性。
我们的结果提供了一项临床前概念验证，支持在靶向治疗方法中抑制RET信号传导对提高EGFR抑制在HNSCC中的疗效所起的作用。
