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

Michelandrea De Cesare, Calogero Lauricella, Silvio Marco Veronese, Denis Cominetti, Claudio Pisano, Franco Zunino, Nadia Zaffaroni, Valentina Zuco

Research output: Contribution to journalArticle

Abstract

Purpose: 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. Experimental Design: 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.Wealso assessed the effects of the combination on EGFR expression at bothmRNAand 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.

Original languageEnglish
Pages (from-to)995-1006
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number4
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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