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

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)...

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Autores principales: Job, Sylvie, de Reyniès, Aurélien, Heller, Betty, Weiss, Amélie, Guérin, Eric, Macabre, Christine, Ledrappier, Sonia, Bour, Cyril, Wasylyk, Christine, Etienne-Selloum, Nelly, Brino, Laurent, Gaiddon, Christian, Wasylyk, Bohdan, Jung, Alain C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627901/
https://www.ncbi.nlm.nih.gov/pubmed/31181806
http://dx.doi.org/10.3390/cancers11060795
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author Job, Sylvie
de Reyniès, Aurélien
Heller, Betty
Weiss, Amélie
Guérin, Eric
Macabre, Christine
Ledrappier, Sonia
Bour, Cyril
Wasylyk, Christine
Etienne-Selloum, Nelly
Brino, Laurent
Gaiddon, Christian
Wasylyk, Bohdan
Jung, Alain C.
author_facet Job, Sylvie
de Reyniès, Aurélien
Heller, Betty
Weiss, Amélie
Guérin, Eric
Macabre, Christine
Ledrappier, Sonia
Bour, Cyril
Wasylyk, Christine
Etienne-Selloum, Nelly
Brino, Laurent
Gaiddon, Christian
Wasylyk, Bohdan
Jung, Alain C.
author_sort Job, Sylvie
collection PubMed
description 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.
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spelling pubmed-66279012019-07-23 Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction Job, Sylvie de Reyniès, Aurélien Heller, Betty Weiss, Amélie Guérin, Eric Macabre, Christine Ledrappier, Sonia Bour, Cyril Wasylyk, Christine Etienne-Selloum, Nelly Brino, Laurent Gaiddon, Christian Wasylyk, Bohdan Jung, Alain C. Cancers (Basel) Article 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. MDPI 2019-06-08 /pmc/articles/PMC6627901/ /pubmed/31181806 http://dx.doi.org/10.3390/cancers11060795 Text en © 2019 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Job, Sylvie
de Reyniès, Aurélien
Heller, Betty
Weiss, Amélie
Guérin, Eric
Macabre, Christine
Ledrappier, Sonia
Bour, Cyril
Wasylyk, Christine
Etienne-Selloum, Nelly
Brino, Laurent
Gaiddon, Christian
Wasylyk, Bohdan
Jung, Alain C.
Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction
title Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction
title_full Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction
title_fullStr Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction
title_full_unstemmed Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction
title_short Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction
title_sort preferential response of basal-like head and neck squamous cell carcinoma cell lines to egfr-targeted therapy depending on ereg-driven oncogenic addiction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627901/
https://www.ncbi.nlm.nih.gov/pubmed/31181806
http://dx.doi.org/10.3390/cancers11060795
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