EGFR相关通路的异常活化可导致抗EGFR单抗耐药。我们的研究显示1.RANKL能激活胃癌细胞的EGFR通路，降低其对抗EGFR单抗的敏感性；2.Gab2能增强RANKL诱导的EGFR活化，c-Src可促进RANKL诱导的c-MET和IGFR活化。其他研究组的研究证实，在破骨细胞中RANK、Gab2和EGFR能够形成复合物；在肿瘤细胞中c-Src可通过激活c-MET等引起抗EGFR治疗耐药。综合上述数据和文献报告，我们推测RANKL可能通过Gab2-EGFR、c-Src-c-MET/IGFR通路，降低胃癌细胞对抗EGFR单抗的敏感性。本研究结果将为进一步明确胃癌对抗EGFR单抗的耐药机制、治疗新靶点和疗效预测因子的筛选、逆转耐药，提供新的科学思路。

The abnormal activation of EGFR and its related signaling pathways might result in gastric cancer cells resistant to anti-EGFR monoclonal antibody. Our study revealed the following results: 1.RANKL could activate EGFR pathway in gastric cancer cells, and decrease sensitivity to anti-EGFR monoclonal antibody.2. Gab2 could enhance RANKL-induced EGFR activation, and c-Src could promote RANKL-induced c-MET and IGFR activation. Other groups reported that RANK, Gab2 and EGFR could formed complex in osteoclast cells，and c-Src was able to induce tumor cells resistance to anti-EGFR treatment through activating c-MET and other receptor tyrosine kinases. Therefore,we propose that RANKL might decrease the sensitivity to anti-EGFR monoclonal antibody in gastric cancer cells via Gab2-EGFR or c-Src-c-MET/IGFR signaling pathways. Our research will provide the novel scientific issue for understanding drug resistant mechanism of anti-EGFR monoclonal antibody in gastric cancer cells, screening the efficacy predictors and restoring the sensitivity.