title: Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells.
abstract: BACKGROUND
  The combination of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib with gemcitabine obtained FDA approval for treating patients with pancreatic cancer. However, duration of response is often limited and there is currently no reliable predictive marker.
  
  
  METHODS
  We determined the sensitivity of a panel of human pancreatic tumour cell lines to treatment with afatinib, erlotinib, monoclonal antibody (mAb) ICR62, and gemcitabine, using the Sulforhodamine B colorimetric assay. The effect of these agents on cell signalling and cell-cycle distribution was determined by western blot and flow cytometry, respectively.
  
  
  RESULTS
  At 200 nM, ICR62 had no effect on growth of these tumour cells with the exception of BxPC-3 cells. BxPC-3 cells were also sensitive to treatment with afatinib and erlotinib with respective IC(50) values of 11 and 1200 nM. Compared with erlotinib, afatinib was also more effective in inhibiting the growth of the other human pancreatic tumour cell lines and in blocking the EGF-induced phosphorylation of tyrosine, EGFR, MAPK, and AKT. When tested in BxPC-3 xenografts, afatinib induced significant delay in tumour growth.
  
  
  CONCLUSIONS
  The superiority of afatinib in this study encourages further investigation on the therapeutic potential of afatinib as a single agent or in combination with gemcitabine in pancreatic cancer.
authors.affiliation: School of Life Sciences, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK.
authors.forename: N
authors.initials: N
authors.lastname: Ioannou
authors.forename: A G
authors.initials: AG
authors.lastname: Dalgleish
authors.forename: A M
authors.initials: AM
authors.lastname: Seddon
authors.forename: D
authors.initials: D
authors.lastname: Mackintosh
authors.forename: U
authors.initials: U
authors.lastname: Guertler
authors.forename: F
authors.initials: F
authors.lastname: Solca
authors.forename: H
authors.initials: H
authors.lastname: Modjtahedi
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003124:Colorimetry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018739:Oncogene Proteins v-erbB; D011799:Quinazolines; D000077716:Afatinib