Translational Therapeutics

BJC Open article

British Journal of Cancer (2011) 105, 1554–1562. doi:10.1038/bjc.2011.396 www.bjcancer.com
Published online 4 October 2011

Anti-tumour activity of afatinib, an irreversible ErbB family blocker, in human pancreatic tumour cells

N Ioannou1, A G Dalgleish2, A M Seddon1, D Mackintosh1, U Guertler3, F Solca3 and H Modjtahedi1

  1. 1School of Life Sciences, Kingston University London, Kingston-upon-Thames, Surrey KT1 2EE, UK
  2. 2Department of Cellular and Molecular Medicine, St George's University of London, London SW17 ORE, UK
  3. 3Boehringer Ingelheim RCV GmbH & Co KG, Vienna A-1121, Austria

Correspondence: Dr H Modjtahedi, E-mail: h.modjtahedi@Kingston.ac.uk

Received 27 June 2011; Revised 31 August 2011; Accepted 12 September 2011
Advance online publication 4 October 2011

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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 200nM, 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 IC50 values of 11 and 1200nM. 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.

Conclusion:

  

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.

Keywords:

afatinib; erlotinib; ICR62; pancreatic cancer