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Open Access Research

Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines

Andrea Cavazzoni1, Roberta R Alfieri1*, Daniele Cretella1, Francesca Saccani1, Luca Ampollini2, Maricla Galetti13, Federico Quaini1, Gallia Graiani1, Denise Madeddu1, Paola Mozzoni13, Elena Galvani1, Silvia La Monica1, Mara Bonelli1, Claudia Fumarola1, Antonio Mutti1, Paolo Carbognani2, Marcello Tiseo4, Elisabetta Barocelli5, Pier Giorgio Petronini1 and Andrea Ardizzoni4

Author Affiliations

1 Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy

2 Department of Surgical Science, University of Parma, Parma, Italy

3 Italian Workers’ Compensation Authority (INAIL) Research Center, University of Parma, Parma, Italy

4 Division of Medical Oncology, University Hospital of Parma, Parma, Italy

5 Department of Pharmacy, University of Parma, Parma, Italy

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Molecular Cancer 2012, 11:91  doi:10.1186/1476-4598-11-91

Published: 12 December 2012

Abstract

Background

The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC.

Results

In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone.

Conclusion

Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.

Keywords:
Lung cancer; EGFR; Erlotinib; Cetuximab; ADCC