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RANKL/RANK pathway abrogates cetuximab sensitivity in gastric cancer cells via activation of EGFR and c-Src

Authors Zhang X, Song Y, Song N, Zhang Y, Zhang L, Wang Y, Wang Z, Qu X, Liu Y

Received 20 April 2016

Accepted for publication 31 August 2016

Published 5 January 2017 Volume 2017:10 Pages 73—83

DOI https://doi.org/10.2147/OTT.S110918

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ru Chen

Peer reviewer comments 3

Editor who approved publication: Dr Faris Farassati

Xiaomeng Zhang,1,3 Yongxi Song,2 Na Song,1,3 Ye Zhang,1,3 Lingyun Zhang,1,3 Yan Wang,1,3 Zhenning Wang,2 Xiujuan Qu,1,3 Yunpeng Liu1,3

1Department of Medical Oncology, 2Department of Surgical Oncology and General Surgery, 3Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, People’s Republic of China

Abstract: Overexpression of EGFR is commonly seen in gastric cancer (GC). However, patients with GC show resistance to anti-EGFR treatments. RAS 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 (P<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.

Keywords: RANKL/RANK, EGFR, cetuximab, c-Src, gastric cancer

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