Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction

Sep 24, 2026

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Epiregulin (EREG) functions as an EGFR and ErbB4 ligand and is linked to head and neck squamous cell carcinoma (HNSCC) progression, poor survival, and responsiveness to anti-EGFR therapy. In the tumor microenvironment, EREG shed by macrophages and cancer-associated fibroblasts may also support resistance. This study silenced EREG in HNSCC models and evaluated growth, clonogenic survival, apoptosis, metabolism, and ferroptosis with or without cetuximab (CTX), validating effects in patient-derived tumoroids. EREG invalidation sensitized cells to CTX, inducing ferroptosis via lipid peroxidation, iron accumulation, and GPX4 loss; combining ferroptosis inducers (RSL3, metformin) with CTX further reduced survival.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

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Abstract

Introduction

cells Article Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction Aude Jehl 1, Ombline Conrad 1, Mickaël Burgy 1,2, Sophie Foppolo 1, Romain Vauchelles 1, Carole Ronzani 3, Nelly Etienne-Selloum 1,4, Marie-Pierre Chenard 5, Aur²lien Danic 6, Thomas Dourlhes 6, Claire Thibault 6, Philippe Schultz 6, Monique Dontenwill 1 and Sophie Martin 1, * Citation: Jehl, A.; Conrad, O.; Burgy, M.; Foppolo, S.; Vauchelles, R.; Ronzani, C.; Etienne-Selloum, N.; Chenard, M.-P.; Danic, A.; Dourlhes, T.; et al. Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction. Cells 2023, 12, 733 . [https://doi.org/10.3390/cells](https://doi.org/10.3390/cells)[ ](https://doi.org/10.3390/cells)12050733 Academic Editors: Julia Bar, Nina Zidar and Piotr Cierpikowski Received: 2 December 2022 Revised: 13 February 2023 Accepted: 20 February 2023 Published: 24 February 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Laboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, France 2 Department of Medical Oncology, Institute of Cancerology Strasbourg Europe, 67200 Strasbourg, France 3 Laboratory of Design and Application of Bioactive Molecules, University of Strasbourg, UMR7199, CNRS, 67400 Illkirch, France 4 Department of Pharmacy, Institute of Cancerology Strasbourg Europe, 67200 Strasbourg, France 5 Department of Pathology, Strasbourg University Hospital, 67200 Strasbourg, France 6 Department of Otolaryngology and Cervico-Facial Surgery, Strasbourg University Hospital, 67200 Strasbourg, France * Correspondence: [sophie.martin@unistra.fr](sophie.martin@unistra.fr); Tel.: +33-36-885-4197; Fax: +33-36-885-4313 Abstract: (1) Background: Epiregulin (EREG) is a ligand of EGFR and ErB4 involved in the development and the progression of various cancers including head and neck squamous cell carcinoma (HNSCC) . Its overexpression in HNSCC is correlated with short overall survival and progressionfree survival but predictive of tumors responding to anti-EGFR therapies. Besides tumor cells, macrophages and cancer-associated ﬁbroblasts shed EREG in the tumor microenvironment to support tumor progression and to promote therapy resistance. Although EREG seems to be an interesting therapeutic target, no study has been conducted so far on the consequences of EREG invalidation regarding the behavior and response of HNSCC to anti-EGFR therapies and, more speciﬁcally, to cetuximab (CTX); (2) Methods: EREG was silenced in various HNSCC cell lines. The resulting phenotype (growth, clonogenic survival, apoptosis, metabolism, ferroptosis) was assessed in the absence or presence of CTX. The data were conﬁrmed in patient-derived tumoroids; (3) Results: Here, we show that EREG invalidation sensitizes cells to CTX. This is illustrated by the reduction in cell survival, the alteration of cell metabolism associated with mitochondrial dysfunction and the initiation of ferroptosis characterized by lipid peroxidation, iron accumulation and the loss of GPX4 . Combining ferroptosis inducers (RSL3 and metformin) with CTX drastically reduces the survival of HNSCC cells but also HNSCC patient-derived tumoroids; (4) Conclusions: The loss of EREG might be considered in clinical settings as a predictive biomarker for patients that might undergo ferroptosisin response to CTX and that might beneﬁt the most from the combination of ferroptosis inducersand CTX. Keywords: head and neck cancers; EREG; ferroptosis; tumoroid; biomarkers; metabolism; autophagy 1. Introduction With nearly 932,000 new cases and 450,000 deaths in 2018 worldwi

FAQs

What is the biological role of EREG in HNSCC and anti-EGFR therapy response?

EREG is a ligand for EGFR/ErbB4 and is associated with HNSCC progression and survival. Its overexpression correlates with responses to anti-EGFR therapies, and microenvironmental shedding may promote resistance.

How was EREG experimentally tested for its effect on CTX sensitivity?

EREG was silenced in multiple HNSCC cell lines, and outcomes including growth, clonogenic survival, apoptosis, metabolism, and ferroptosis were assessed with and without cetuximab (CTX). Results were confirmed using patient-derived tumoroids.

What mechanism links EREG loss to increased CTX sensitivity?

EREG invalidation reduced cell survival and triggered ferroptosis characterized by lipid peroxidation, iron accumulation, and loss of GPX4. It also involved metabolic changes associated with mitochondrial dysfunction.

Why does combining ferroptosis inducers with CTX improve outcomes?

The combination of ferroptosis inducers (RSL3 and metformin) with CTX drastically reduced survival of HNSCC cells and patient-derived tumoroids, indicating a synergistic effect through ferroptosis activation.

Sep 24, 2026

Uploaded by Jiven