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Cancers (Basel). 2019 Jun 8;11(6). pii: E795. doi: 10.3390/cancers11060795.

Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction.

Author information

1
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, 75013 Paris, France. Sylvie.Job@ligue-cancer.net.
2
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre le Cancer, 75013 Paris, France. Aurelien.DeReynies@ligue-cancer.net.
3
Institut de Génétique et de Biologie Moléculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. heller@igbmc.fr.
4
Institut de Génétique et de Biologie Moléculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. weiss@igbmc.fr.
5
Laboratoire de Biochimie et Biologie Moléculaire, Hôpitaux Universitaires de Strasbourg, 67098 Strasbourg, France. eric.guerin@chru-strasbourg.fr.
6
Université de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. eric.guerin@chru-strasbourg.fr.
7
Université de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. cmacabre@strasbourg.unicancer.fr.
8
Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. cmacabre@strasbourg.unicancer.fr.
9
Université de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. sledrappier@strasbourg.unicancer.fr.
10
Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. sledrappier@strasbourg.unicancer.fr.
11
Université de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. cbour@strasbourg.unicancer.fr.
12
Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. cbour@strasbourg.unicancer.fr.
13
Institut de Génétique et de Biologie Moléculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. christannie67@gmail.com.
14
Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. nelly.etienne-selloum@unistra.fr.
15
UMR 7021 CNRS/Unistra, Laboratoire de Bioimagerie et Pathologies (LBP), Faculté de Pharmacie, 67401 Illkirch, France. nelly.etienne-selloum@unistra.fr.
16
Institut de Génétique et de Biologie Moléculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. brino@igbmc.fr.
17
Université de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. gaiddon@unistra.fr.
18
Institut de Génétique et de Biologie Moléculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. boh@igbmc.fr.
19
Université de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. AJung@strasbourg.unicancer.fr.
20
Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. AJung@strasbourg.unicancer.fr.

Abstract

The management of locally advanced head and neck squamous cell carcinoma (HNSCC) with Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), achieves only moderate response rates, and clinical trials that evaluated EGFR-blockade with tyrosine kinase inhibitors (TKI) yielded disappointing results. Inter-tumor heterogeneity may hinder the therapeutic efficiency of anti-EGFR treatments. HNSCC heterogeneity was addressed in several studies, which all converged towards the definition of molecular subgroups. They include the basal subgroup, defined by the deregulated expression of factors involved in the EGFR signaling pathway, including the epiregulin EGFR ligand encoded by the EREG gene. These observations indicate that basal tumors could be more sensitive to anti-EGFR treatments. To test this hypothesis, we performed a screen of a representative collection of basal versus non-basal HNSCC cell lines for their sensitivity to several anti-EGFR drugs (Cetuximab, Afatinib, and Gefitinib), tested as monotherapy or in combination with drugs that target closely-linked pathways [Mitogen-activated protein kinase kinase/ extracellular signal-regulated kinases (MEK), mammalian Target of Rapamycine (mTOR) or Human Epidermal growth factor Receptor 2 (HER2)]. Basal-like cell lines were found to be more sensitive to EGFR blockade alone or in combination with treatments that target MEK, mTOR, or HER2. Strikingly, the basal-like status was found to be a better predictor of cell response to EGFR blockade than clinically relevant mutations [e.g., cyclin-dependent kinase Inhibitor 2A (CDKN2A)]. Interestingly, we show that EGFR blockade inhibits EREG expression, and that EREG knock-down decreases basal cell clonogenic survival, suggesting that EREG expression could be a predictive functional marker of sensitivity to EGFR blockade in basal-like HNSCC.

KEYWORDS:

EGFR; EREG; cancer subgroups; drug sensitivity; head and neck squamous cell carcinoma; treatment combinations

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