Figure S6 from AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer

Conticelli, Daniela; Volante, Marco; Pietrantonio, Filippo; Orrù, Claudia; Olivero, Martina; Nottegar, Alessia; Borghi, Felice; Baiocchi, Gian L.; Crotti, Giovanni; Fumagalli Romario, Uberto; De Manzoni, Giovanni; Reddavid, Rossella; Porporato, Roberta; Kılıç, Dinçer; Ghione, Rebecca; Calabrò, Erika; Petty, Russell; Corso, Simona; Giordano, Silvia; Migliore, Cristina

doi:10.1158/0008-5472.29918891

Figure S6 from AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer

https://doi.org/10.1158/0008-5472.29918891

journal contribution

posted on 2025-08-15, 08:02 authored by Daniela Conticelli, Marco Volante, Filippo Pietrantonio, Claudia Orrù, Martina Olivero, Alessia Nottegar, Felice Borghi, Gian L. Baiocchi, Giovanni Crotti, Uberto Fumagalli Romario, Giovanni De Manzoni, Rossella Reddavid, Roberta Porporato, Dinçer Kılıç, Rebecca Ghione, Erika Calabrò, Russell Petty, Simona Corso, Silvia Giordano, Cristina Migliore

<p>AREG and EREG RNAscope staining and quantification.</p>

Funding

Fondazione AIRC per la ricerca sul cancro ETS (AIRC)

Ministero dell'Università e della Ricerca (MUR)

Cassa di Risparmio di Torino

Ricerchiamo ONLUS

Ministero della Salute (Italy Ministry of Health)

History

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DOI - Is supplement to AREG and EREG Are Predictive Biomarkers of Response to EGFR Inhibition in Gastroesophageal Cancer

ARTICLE ABSTRACT

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. 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.