title: ErbB expression, activation, and inhibition with lapatinib and tyrphostin (AG825) in human vestibular schwannomas.
abstract: BACKGROUND
  Pharmacologic agents targeted against the ErbB family, or the intracellular pathways that mediate their effects, could slow clinical progression of vestibular schwannoma (VS) in patients where other modalities carry a high risk-to-benefit ratio.
  
  
  OBJECTIVE
  Determine the identity of the predominant ErbB dimer partners in VS tumors and assess the effects of targeted inhibition of the ErbB molecules on VS growth and proliferation, as well as apoptosis.
  
  
  METHODS
  Academic tertiary referral center.
  
  
  METHODS
  Coimmunoprecipitation and Western blotting of VS tissue, in vitro BrdU assays of proliferation in the presence of lapatinib and tyrphostin (AG825) using primary VS cultures, and annexin V cell death assays and cell cycle assays using propidium iodide staining were performed on HEI193 cell line derived from an neurofibromatosis type 2-associated VS.
  
  
  RESULTS
  Activated ErbB family receptor heterodimers in VS contain predominantly epidermal growth factor receptor (EGFR) and ErbB2. A robust, dose-dependent inhibition of VS growth and proliferation with the dual EGFR/ErbB2 inhibitor, lapatinib, was demonstrated. Lapatinib also inhibited EGF-induced VS proliferation. The selective ErbB2 inhibitor, AG825, inhibited growth to a lesser extent. HEI193 demonstrated apoptosis after lapatinib treatment.
  
  
  CONCLUSIONS
  Dual EGFR and ErbB2 inhibition with lapatinib or combination therapy may provide therapeutic benefit in VS treatment, but further studies are necessary.
authors.affiliation: Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, California, USA.
authors.forename: Zana K
authors.initials: ZK
authors.lastname: Ahmad
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Brown
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Cueva
authors.forename: Allen F
authors.initials: AF
authors.lastname: Ryan
authors.forename: Joni K
authors.initials: JK
authors.lastname: Doherty
mesh_terms: D052160:Benzothiazoles / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D000077341:Lapatinib; D009464:Neuroma, Acoustic / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D052160:Benzothiazoles; D004815:Epidermal Growth Factor; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C098214:tyrphostin AG825; C508053:ERBB2 protein, human