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

Author:

Jehl Aude1ORCID,Conrad Ombline1ORCID,Burgy Mickaël12ORCID,Foppolo Sophie1ORCID,Vauchelles Romain1,Ronzani Carole3,Etienne-Selloum Nelly14ORCID,Chenard Marie-Pierre5,Danic Aurélien6,Dourlhes Thomas6,Thibault Claire6,Schultz Philippe6,Dontenwill Monique1ORCID,Martin Sophie1ORCID

Affiliation:

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

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 progression-free 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 ferroptosis in response to CTX and that might benefit the most from the combination of ferroptosis inducers and CTX.

Funder

Interdisciplinary Thematic Institute program of the University of Strasbourg

Ligue Contre le Cancer, Conférence de coordination interrégionale du Grand Est programme-inter region

URPS Chirurgiens Dentistes Grand Est

Publisher

MDPI AG

Subject

General Medicine

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