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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Epidermal growth factor receptor (EGFR) overexpression is common in gastric cancer (GC).
• Patients with GC often exhibit resistance to anti-EGFR treatments, which is not fully explained by rare RAS mutations.
• The role of the RANKL/RANK pathway in mediating anti-EGFR treatment resistance in GC is currently unknown.

Purpose of the Study:

• To investigate the effect of the RANKL/RANK pathway on the EGFR pathway in gastric cancer.
• To explore the potential role of the RANKL/RANK pathway in resistance to anti-EGFR treatments in GC.

Main Methods:

• Immunohistochemical staining was used to detect EGFR and RANK expression in GC tissues.
• In vitro studies were conducted using GC cells to assess the impact of RANKL on EGFR pathway activation and cetuximab sensitivity.
• Gene knockdown and pharmacological inhibitors (RANKL inhibitor, c-SRC inhibitor) were employed to investigate pathway mediation.

Main Results:

• A positive correlation was observed between EGFR and RANK expression in GC tissues (P<0.001).
• RANKL stimulation in GC cells led to EGFR pathway activation and reduced sensitivity to cetuximab.
• Inhibition of RANK, RANKL, or c-SRC reversed RANKL-induced EGFR activation and restored cetuximab sensitivity.

Conclusions:

• The RANKL/RANK pathway activates the EGFR pathway in gastric cancer cells.
• This activation confers resistance to anti-EGFR treatments, such as cetuximab.
• Targeting the RANKL/RANK pathway, potentially via c-SRC, could be a therapeutic strategy to overcome resistance in GC.