PMID- 27086488 OWN - NLM STAT- MEDLINE DCOM- 20170130 LR - 20181202 IS - 1879-0593 (Electronic) IS - 1368-8375 (Linking) VI - 56 DP - 2016 May TI - Growth factor expression mediates resistance to EGFR inhibitors in head and neck squamous cell carcinomas. PG - 62-70 LID - S1368-8375(16)30001-X [pii] LID - 10.1016/j.oraloncology.2016.03.008 [doi] AB - OBJECTIVES: Epidermal growth factor receptor (EGFR)-targeted therapy is frequently used in the treatment of advanced head and neck squamous cell carcinoma (HNSCC). However, constitutive or acquired resistance is common and underlying resistance mechanisms remain poorly understood. We investigated the expression levels of growth factors (GF) in tumor-associated stroma and tumor from HNSCC patients and determined the influence of GFs on EGFR inhibitor efficacy in vitro. MATERIALS AND METHODS: The Chicago HNC Genomic Cohort (CHGC) was queried for GF and receptor tyrosine kinase (RTK) expression. Viability assays were used to evaluate the effect of EGFR inhibition (gefitinib), GF treatment, or both in HNSCC cell lines. Caspase-based assays were used to measure apoptotic activity. Expression of RTKs was determined and correlated with GF treatment effects. RESULTS: Amphiregulin (AREG), transforming growth factor (TGFbeta1), insulin like growth factor (IGF1), fibroblast growth factors (FGF1/FGF2) and the corresponding RTKs were highly expressed in 30-50% of HNSCC, and expression was usually concurrent. While EGFR inhibition was markedly efficacious in HNC cell lines (HN5/HN13/H400/SCC61), co-treatment with most GFs increased viability up to 100%. Only TGFbeta1 treatment was additive to EGFR inhibition. GFs also reduced apoptotic effects of EGFR inhibition. RTK expression showed strong positive correlation with respective GF treatment effect for IGF1-IGF1R, less strong for HGF-MET/AREG-EGFR and a moderate negative correlation for TGFbeta1-TGFBR1/2. CONCLUSION: High expression of GFs/RTKs occurs in HNSCC. Co-expression is common. GF expression contributes to EGFR inhibition resistance in our model system, and may be a common mechanism of constitutive or acquired resistance to EGFR inhibition in HNSCC. CI - Copyright (c) 2016. Published by Elsevier Ltd. FAU - Tepper, Susanne R AU - Tepper SR AD - Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Section Translational and Experimental Head and Neck Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany. Electronic address: susanne@seiwertlab.com. FAU - Zuo, Zhixiang AU - Zuo Z AD - Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: zhixiang@seiwertlab.com. FAU - Khattri, Arun AU - Khattri A AD - Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: arun@seiwertlab.com. FAU - Hess, Jochen AU - Hess J AD - Section Translational and Experimental Head and Neck Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address: j.hess@dkfz-heidelberg.de. FAU - Seiwert, Tanguy Y AU - Seiwert TY AD - Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: tseiwert@medicine.bsd.uchicago.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160326 PL - England TA - Oral Oncol JT - Oral oncology JID - 9709118 RN - 0 (Intercellular Signaling Peptides and Proteins) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM CIN - Oral Oncol. 2016 Aug;59:e12-e14. PMID: 27302885 MH - Carcinoma, Squamous Cell/*drug therapy/pathology MH - Cell Line, Tumor MH - *Drug Resistance, Neoplasm MH - ErbB Receptors/*antagonists & inhibitors MH - Head and Neck Neoplasms/*drug therapy/pathology MH - Humans MH - Intercellular Signaling Peptides and Proteins/*metabolism OTO - NOTNLM OT - Drug resistance OT - Epidermal growth factor receptor OT - Gefitinib OT - Head and neck cancer OT - Squamous cell carcinoma OT - Tumor microenvironment EDAT- 2016/04/19 06:00 MHDA- 2017/01/31 06:00 CRDT- 2016/04/19 06:00 PHST- 2015/08/02 00:00 [received] PHST- 2016/03/02 00:00 [revised] PHST- 2016/03/12 00:00 [accepted] PHST- 2016/04/19 06:00 [entrez] PHST- 2016/04/19 06:00 [pubmed] PHST- 2017/01/31 06:00 [medline] AID - S1368-8375(16)30001-X [pii] AID - 10.1016/j.oraloncology.2016.03.008 [doi] PST - ppublish SO - Oral Oncol. 2016 May;56:62-70. doi: 10.1016/j.oraloncology.2016.03.008. Epub 2016 Mar 26.