EGFR is a potential therapeutic target in gastroesophageal cancer. However, negative results from several phase II/III clinical trials have hindered the approval of EGFR inhibitors for treating gastroesophageal adenocarcinoma. Preclinical and clinical results have shown that EGFR targeting is effective in patients with gastroesophageal adenocarcinoma harboring EGFR amplification. Retrospective analyses also suggest that a subset of patients with gastroesophageal adenocarcinoma lacking EGFR amplification may benefit from the treatment, thus underscoring the need to identify reliable predictive biomarkers of response. Through the screening of 27 gastroesophageal adenocarcinoma primary cancer cell lines and 10 patient-derived xenograft models, we identified a subset of gastroesophageal adenocarcinoma lacking EGFR quantitative alterations but sensitive to EGFR targeting. Molecular characterization of the sensitive models revealed overexpression of the EGFR ligand amphiregulin (AREG) or epiregulin (EREG). Post hoc analysis of patients on the Cancer Esophagus Gefitinib trial treated with the EGFR inhibitor gefitinib demonstrated a significant correlation between overall survival and AREG/EREG expression level. No predictive power of EGFR ligand expression was observed in the presence of KRAS mutations. In conclusion, this study proposes the existence of a subgroup of patients with gastroesophageal adenocarcinoma with susceptibility to EGFR inhibition driven by overexpression of the EGFR ligands AREG and EREG.
Significance: Elevated levels of AREG or EREG in gastroesophageal cancer confers sensitivity to EGFR inhibition, providing a low-toxicity treatment option for the subpopulation of patients overexpressing the EGFR ligands.
©2025 The Authors; Published by the American Association for Cancer Research.