title: HRAS mutations and resistance to the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in head and neck squamous cell carcinoma cells.
abstract: BACKGROUND
  The purpose of this study was to identify mechanisms of innate resistance to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib, in a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. Specifically, we analyzed the role of HRAS mutations in erlotinib resistance.
  
  
  METHODS
  Erlotinib sensitivity was determined by methyl thiazolyl-tetrazolium (MTT) assays. Molecular signaling pathways and somatic mutations were examined. Changes in sensitivity after modulation of HRAS expression were evaluated.
  
  
  RESULTS
  All 7 cell lines were wild-type for EGFR and KRAS regardless of erlotinib sensitivity; however, 1 erlotinib-resistant cell line (HN31) harbored an HRAS G12D mutation. Downregulation of HRAS expression by small interfering RNA (siRNA) or short hairpin RNA (shRNA) in HN31 led to increased erlotinib sensitivity in vitro and in vivo. Transfection of activating HRAS-mutant (G12D and G12V) constructs into erlotinib-sensitive cell lines made them more resistant to erlotinib.
  
  
  CONCLUSIONS
  Activating HRAS mutations can confer erlotinib resistance in an HRAS mutant HNSCC cell line.
authors.affiliation: Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Otolaryngology - Head and Neck Surgery, Seoul National University Hospital and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: J Hun
authors.initials: JH
authors.lastname: Hah
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Pickering
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Frederick
authors.forename: Genevieve A
authors.initials: GA
authors.lastname: Andrews
authors.forename: Samar A
authors.initials: SA
authors.lastname: Jasser
authors.forename: David R
authors.initials: DR
authors.lastname: Fooshee
authors.forename: Zvonimir L
authors.initials: ZL
authors.lastname: Milas
authors.forename: Chad
authors.initials: C
authors.lastname: Galer
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sano
authors.forename: William N
authors.initials: WN
authors.lastname: William
authors.forename: Edward
authors.initials: E
authors.lastname: Kim
authors.forename: John
authors.initials: J
authors.lastname: Heymach
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.forename: Vali
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Myers
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000187:drug effects / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D014162:Transfection
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: HRAS; epidermal growth factor receptor; erlotinib; head and neck squamous cell carcinoma; resistance