title: Synergistic antitumor activity of cetuximab and namitecan in human squamous cell carcinoma models relies on cooperative inhibition of EGFR expression and depends on high EGFR gene copy number.
abstract: OBJECTIVE
  Despite the frequent overexpression of epidermal growth factor receptor (EGFR) in squamous cell carcinoma (SCC), the efficacy of cetuximab alone is limited. Given the marked activity of namitecan, a hydrophilic camptothecin, against SCC models, the present study was performed to explore the efficacy of the cetuximab-namitecan combination in a panel of SCC models.
  
  
  METHODS
  We examined the antiproliferative and antitumor activities of the cetuximab-namitecan combination in four SCC models characterized by a different EGFR gene copy number/EGFR protein level. We also assessed the effects of the combination on EGFR expression at both mRNA and protein levels and investigated the molecular basis of the interaction between the two agents.
  
  
  RESULTS
  Cetuximab and namitecan exhibited synergistic effects, resulting in potentiation of cell growth inhibition and, most importantly, enhanced therapeutic efficacy, with high cure rates in three SCC models characterized by high EGFR gene copy number, without increasing toxicity. The synergistic antitumor effect was also observed with the cetuximab-irinotecan combination. At the molecular level, the two agents produced a cooperative effect resulting in complete downregulation of EGFR. Interestingly, when singly administered, the camptothecin was able to strongly decrease EGFR expression mainly by transcriptional inhibition.
  
  
  CONCLUSIONS
  Our results (i) demonstrate a marked efficacy of the cetuximab-namitecan combination, which reflects a complete abrogation of EGFR expression as a critical determinant of the therapeutic improvement, in SCC preclinical models, and (ii) suggest EGFR gene copy number as a possible marker to be used for patient selection in the clinical setting.
authors: Authors' Affiliations: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale per lo Studio e la Cura dei Tumori; Molecular Pathology Unit, Ospedale Niguarda Ca' Grande, Milan; and Sigma-Tau S.p.A., Pomezia, Italy.
authors: Michelandrea
authors: M
authors: De Cesare
authors: Calogero
authors: C
authors: Lauricella
authors: Silvio Marco
authors: SM
authors: Veronese
authors: Denis
authors: D
authors: Cominetti
authors: Claudio
authors: C
authors: Pisano
authors: Franco
authors: F
authors: Zunino
authors: Nadia
authors: N
authors: Zaffaroni
authors: Valentina
authors: V
authors: Zuco
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D056915:DNA Copy Number Variations; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D018628:Gene Dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; C531200:namitecan; D002166:Camptothecin