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

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.

Positive Cross-Talk Between CXC Chemokine Receptor 4 (CXCR4) and Epidermal Growth Factor Receptor (EGFR) Promotes Gastric Cancer Metastasis via the Nuclear Factor kappa B (NF-kB)-Dependent Pathway

“…In our study, 56 gastric cancer specimens were collected. Our results suggested that patients with co-expression of CXCR4 and EGFR were more likely to have lymph node metastasis and poor prognosis, which is consistent with previous studies [ 4 , 13 ]. Furthermore, the impact of co-expression of CXCR4 and EGFR on prognosis in gastric cancer was investigated.…”

“…Immunohistochemical staining was performed as described previously [ 4 , 13 ]. Positivity (high expression) was defined as >10% of tumor cells showing staining in the sample.…”

RANKL/RANK promotes the migration of gastric cancer cells by interacting with EGFR

“…RANKL stimulates RANK and has effects on the migration and invasion of cancer cells. Furthermore, RANKL/RANK function as predictors of tumorigenesis and prognosis in many solid tumors, including breast cancer and GC [18–20]. RANKL and its receptor, RANK, can be modulated by EGFR signaling [21].…”

Differential expression of DUSP2 in left- and right-sided colon cancer is associated with poor prognosis in colorectal cancer

“…CRC is the most common type of malignancy with the third highest incidence and mortality rates among all diagnosed cases of cancer worldwide ( 18 , 19 ). Cetuximab combined with chemotherapy has demonstrated therapeutic efficacy in patients with metastatic CRC with all RAS wild-type tumors ( 20 ). However, the efficacy of cetuximab is limited by the development of resistance mechanisms in cancer cells ( 21 ).…”