title: Reduced proliferation and colony formation of head and neck squamous cell carcinoma (HNSCC) after dual targeting of EGFR and hedgehog pathways.
abstract: The hedgehog signalling pathway (Hh) is frequently active in head and neck squamous cell carcinoma (HNSCC). Overexpressed Hh associates with poor prognosis. The Hh inhibitor vismodegib targets smoothened, and based on molecular data, may prevent resistance to EGFR targeting.
  
  
  
  To elucidate potential roles of vismodegib in HNSCC therapy, its sole effects and those combined with cisplatin, docetaxel, and cetuximab on HNSCC cell lines were assessed by MTT metabolisation and BrdU incorporation. Colony formation (CF) of primary HNSCC cells was studied utilizing the FLAVINO-protocol. Combinatory effects were analysed regarding antagonism, additivity or synergism. Associations between the ex vivo detected mode of action of vismodegib with other treatments related to patient characteristics were assessed and progression-free survival (PFS) in patient groups compared using Kaplan-Meier curves.
  
  
  
  Vismodegib suppressed BrdU incorporation significantly stronger than MTT turnover; CF was significantly inhibited at ≥20 µM vismodegib while concentrations <20 µM acted hormetic. Combining 20 µM vismodegib plus docetaxel (T), cisplatin (P), and cetuximab (E), additively enhanced anti-tumoral activity in HNSCC samples from patients with superior PFS highlighting a potential role for ex-vivo testing of this combination for use as a prognostic classifier.
  
  
  
  We provide ex-vivo evidence for vismodegib's potential in HNSCC therapies, especially if combined with cetuximab, cisplatin and docetaxel.
authors.affiliation: ENT-Research Laboratory, Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Liebigstraße 21, Liebigstr. 10-14, 04103, Leipzig, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Liebig
authors.affiliation: ENT-Research Laboratory, Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Liebigstraße 21, Liebigstr. 10-14, 04103, Leipzig, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Günther
authors.affiliation: ENT-Research Laboratory, Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Liebigstraße 21, Liebigstr. 10-14, 04103, Leipzig, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Kolb
authors.affiliation: ENT-Research Laboratory, Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Liebigstraße 21, Liebigstr. 10-14, 04103, Leipzig, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Mozet
authors.affiliation: ENT-Research Laboratory, Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Liebigstraße 21, Liebigstr. 10-14, 04103, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Boehm
authors.affiliation: ENT-Research Laboratory, Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Liebigstraße 21, Liebigstr. 10-14, 04103, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dietz
authors.affiliation: ENT-Research Laboratory, Clinic for Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig, Liebigstraße 21, Liebigstr. 10-14, 04103, Leipzig, Germany. gunnar.wichmann@medizin.uni-leipzig.de.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Wichmann
mesh_terms: D000813:Anilides / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Erivedge®; Head and neck cancer (HNC); Head and neck squamous cell carcinoma (HNSCC); Hedgehog signalling pathway; SMO; Vismodegib