title: Combined use of anti-ErbB monoclonal antibodies and erlotinib enhances antibody-dependent cellular cytotoxicity of wild-type erlotinib-sensitive NSCLC cell lines.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
authors.forename: Daniele
authors.initials: D
authors.lastname: Cretella
authors.forename: Francesca
authors.initials: F
authors.lastname: Saccani
authors.forename: Luca
authors.initials: L
authors.lastname: Ampollini
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.forename: Gallia
authors.initials: G
authors.lastname: Graiani
authors.forename: Denise
authors.initials: D
authors.lastname: Madeddu
authors.forename: Paola
authors.initials: P
authors.lastname: Mozzoni
authors.forename: Elena
authors.initials: E
authors.lastname: Galvani
authors.forename: Silvia
authors.initials: S
authors.lastname: La Monica
authors.forename: Mara
authors.initials: M
authors.lastname: Bonelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Fumarola
authors.forename: Antonio
authors.initials: A
authors.lastname: Mutti
authors.forename: Paolo
authors.initials: P
authors.lastname: Carbognani
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055550:Protein Stability / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab