Zhang Xiaomeng, Song Yongxi, Song Na, Zhang Ye, Zhang Lingyun, Wang Yan, Wang Zhenning, Qu Xiujuan, Liu Yunpeng
Department of Medical Oncology; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, People's Republic of China.
Department of Surgical Oncology and General Surgery.
Onco Targets Ther. 2017 Jan 5;10:73-83. doi: 10.2147/OTT.S110918. eCollection 2017.
Overexpression of EGFR is commonly seen in gastric cancer (GC). However, patients with GC show resistance to anti-EGFR treatments. mutations are rare in GC and cannot explain de novo resistance to EGFR treatments. Therefore, it is particularly important to explore the mechanisms of resistance to anti-EGFR treatments. The RANKL activates the EGFR pathway in osteoclasts, and the RANK is expressed in gastric carcinoma. Whether the RANKL/RANK pathway has an effect on the EGFR pathway in GC remains unknown. Expressions of EGFR and RANK in GC tissues were detected using immunohistochemical staining. Nineteen patients (28%) showed high-level RANKL expression, and 33 patients (48%) showed high-level RANK expression. There was a positive correlation between expression of EGFR and RANK (<0.001). In an in vitro study, RANKL induced activation of the EGFR pathway and further abrogated cetuximab sensitivity in GC cells. Knockdown of RANK or use of the RANKL inhibitor enhanced cetuximab effect by decreasing RANKL-induced EGFR activation. Furthermore, we showed that c-SRC mediated the EGFR activation induced by the RANKL/RANK pathway and that c-SRC inhibitor reversed the suppression of RANKL on the effect of cetuximab. In conclusion, our results suggest that in GC cells, the RANKL/RANK pathway activates the EGFR pathway and thereby causes resistance to anti-EGFR treatments.
表皮生长因子受体（EGFR）的过表达在胃癌（GC）中很常见。然而，GC患者对抗EGFR治疗表现出耐药性。EGFR突变在GC中很少见，无法解释对EGFR治疗的原发性耐药。因此，探索抗EGFR治疗的耐药机制尤为重要。核因子κB受体活化因子配体（RANKL）在破骨细胞中激活EGFR通路，而RANK在胃癌中表达。RANKL/RANK通路是否对GC中的EGFR通路有影响尚不清楚。采用免疫组织化学染色检测GC组织中EGFR和RANK的表达。19例患者（28%）表现为高水平RANKL表达，33例患者（48%）表现为高水平RANK表达。EGFR和RANK的表达之间存在正相关（<0.001）。在一项体外研究中，RANKL诱导EGFR通路激活，并进一步消除了GC细胞中西妥昔单抗的敏感性。敲低RANK或使用RANKL抑制剂可通过降低RANKL诱导的EGFR激活来增强西妥昔单抗的作用。此外，我们发现c-SRC介导了RANKL/RANK通路诱导的EGFR激活，并且c-SRC抑制剂逆转了RANKL对西妥昔单抗作用的抑制。总之，我们的结果表明，在GC细胞中，RANKL/RANK通路激活EGFR通路，从而导致对抗EGFR治疗产生耐药性。
