PMID- 31181806 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 11 IP - 6 DP - 2019 Jun 8 TI - Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction. LID - 10.3390/cancers11060795 [doi] LID - 795 AB - 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. FAU - Job, Sylvie AU - Job S AD - Programme Cartes d'Identite des Tumeurs (CIT), Ligue Nationale Contre le Cancer, 75013 Paris, France. Sylvie.Job@ligue-cancer.net. FAU - Reynies, Aurelien de AU - Reynies A AD - Programme Cartes d'Identite des Tumeurs (CIT), Ligue Nationale Contre le Cancer, 75013 Paris, France. Aurelien.DeReynies@ligue-cancer.net. FAU - Heller, Betty AU - Heller B AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. heller@igbmc.fr. FAU - Weiss, Amelie AU - Weiss A AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. weiss@igbmc.fr. FAU - Guerin, Eric AU - Guerin E AD - Laboratoire de Biochimie et Biologie Moleculaire, Hopitaux Universitaires de Strasbourg, 67098 Strasbourg, France. eric.guerin@chru-strasbourg.fr. AD - Universite de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. eric.guerin@chru-strasbourg.fr. FAU - Macabre, Christine AU - Macabre C AD - Universite de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. cmacabre@strasbourg.unicancer.fr. AD - Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. cmacabre@strasbourg.unicancer.fr. FAU - Ledrappier, Sonia AU - Ledrappier S AD - Universite de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. sledrappier@strasbourg.unicancer.fr. AD - Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. sledrappier@strasbourg.unicancer.fr. FAU - Bour, Cyril AU - Bour C AD - Universite de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. cbour@strasbourg.unicancer.fr. AD - Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. cbour@strasbourg.unicancer.fr. FAU - Wasylyk, Christine AU - Wasylyk C AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. christannie67@gmail.com. FAU - Etienne-Selloum, Nelly AU - Etienne-Selloum N AD - Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. nelly.etienne-selloum@unistra.fr. AD - UMR 7021 CNRS/Unistra, Laboratoire de Bioimagerie et Pathologies (LBP), Faculte de Pharmacie, 67401 Illkirch, France. nelly.etienne-selloum@unistra.fr. FAU - Brino, Laurent AU - Brino L AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. brino@igbmc.fr. FAU - Gaiddon, Christian AU - Gaiddon C AD - Universite de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. gaiddon@unistra.fr. FAU - Wasylyk, Bohdan AU - Wasylyk B AD - Institut de Genetique et de Biologie Moleculaire et Cellulaire IGBMC, UMR 7104 CNRS-UdS, U.1258 INSERM, 1 rue Laurent Fries, BP 10142, 67404 Illkirch cedex, France. boh@igbmc.fr. FAU - Jung, Alain C AU - Jung AC AD - Universite de Strasbourg, Inserm, UMR_S1113, 67200 Strasbourg, France. AJung@strasbourg.unicancer.fr. AD - Centre de Lutte Contre le Cancer Paul Strauss, 67000 Strasbourg, France. AJung@strasbourg.unicancer.fr. LA - eng PT - Journal Article DEP - 20190608 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC6627901 OTO - NOTNLM OT - EGFR OT - EREG OT - cancer subgroups OT - drug sensitivity OT - head and neck squamous cell carcinoma OT - treatment combinations COIS- The authors declare no conflict of interest. EDAT- 2019/06/12 06:00 MHDA- 2019/06/12 06:01 PMCR- 2019/06/08 CRDT- 2019/06/12 06:00 PHST- 2019/05/03 00:00 [received] PHST- 2019/06/04 00:00 [revised] PHST- 2019/06/06 00:00 [accepted] PHST- 2019/06/12 06:00 [entrez] PHST- 2019/06/12 06:00 [pubmed] PHST- 2019/06/12 06:01 [medline] PHST- 2019/06/08 00:00 [pmc-release] AID - cancers11060795 [pii] AID - cancers-11-00795 [pii] AID - 10.3390/cancers11060795 [doi] PST - epublish SO - Cancers (Basel). 2019 Jun 8;11(6):795. doi: 10.3390/cancers11060795.