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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Molecular Cancer 1/2012

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

Zeitschrift:
Molecular Cancer > Ausgabe 1/2012
Autoren:
Andrea Cavazzoni, Roberta R Alfieri, Daniele Cretella, Francesca Saccani, Luca Ampollini, Maricla Galetti, Federico Quaini, Gallia Graiani, Denise Madeddu, Paola Mozzoni, Elena Galvani, Silvia La Monica, Mara Bonelli, Claudia Fumarola, Antonio Mutti, Paolo Carbognani, Marcello Tiseo, Elisabetta Barocelli, Pier Giorgio Petronini, Andrea Ardizzoni
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1476-4598-11-91) contains supplementary material, which is available to authorized users.
Andrea Cavazzoni, Roberta R Alfieri contributed equally to this work.

Competing interest

All authors declare that they have no competing interests.

Authors’ contribution

AC carried out ADCC experiments, interpreted the results and assisted with the draft of the manuscript; DC isolated and cultured NK cells and carried out flow cytometry analysis; FS, LA and PC performed the in vivo studies; PM carried out RT-PCR experiments; MG and MB carried out Western blot analysis; EG performed the statistical analysis, SLM and CF carried out cell growth experiments; FQ, GG and DM carried out immunohistochemical analysis; AM, MT, EB and PGP critically revised the manuscript; AA designed the project and assisted with the draft of the manuscript; RRA, analyzed the results and wrote the manuscript. All authors read and approved the final manuscript.

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.
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 9
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Literatur
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