title: Growth factor expression mediates resistance to EGFR inhibitors in head and neck squamous cell carcinomas.
abstract: OBJECTIVE
  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.
  
  
  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 (TGFβ1), 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 TGFβ1 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 TGFβ1-TGFBR1/2.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Susanne R
authors.initials: SR
authors.lastname: Tepper
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: zhixiang@seiwertlab.com.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zuo
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: arun@seiwertlab.com.
authors.forename: Arun
authors.initials: A
authors.lastname: Khattri
authors.affiliation: 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.
authors.forename: Jochen
authors.initials: J
authors.lastname: Heß
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. Electronic address: tseiwert@medicine.bsd.uchicago.edu.
authors.forename: Tanguy Y
authors.initials: TY
authors.lastname: Seiwert
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D066246:ErbB Receptors
keywords: Drug resistance; Epidermal growth factor receptor; Gefitinib; Head and neck cancer; Squamous cell carcinoma; Tumor microenvironment