title: CCI-779 (Temsirolimus) exhibits increased anti-tumor activity in low EGFR expressing HNSCC cell lines and is effective in cells with acquired resistance to cisplatin or cetuximab.
abstract: BACKGROUND
  The mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role in numerous cellular processes involving growth, proliferation and survival. The purpose of this study was to investigate the anti-tumoral effect of the mTOR inhibitor (mTORi) CCI-779 in HNSCC cell lines and its potency in cisplatin- and cetuximab-resistant cells.
  
  
  METHODS
  A panel of 10 HNSCC cell lines with differences in TP53 mutational status and basal cisplatin sensitivity and two isogenic models of acquired resistance to cisplatin and cetuximab, respectively were studied. Cell survival after treatment with CCI-779, cisplatin and cetuximab alone or in combination was determined by MTT assays. Potential predictive biomarkers for tumor cell sensitivity to CCI-779 were evaluated.
  
  
  RESULTS
  We observed considerable heterogeneity in sensitivity of HNSCC cell lines to CCI-779 monotherapy. Sensitivity was observed in TP53 mutated as well as wild-type cell lines. Total and p-EGFR expression levels but not the basal activity of the mTOR and MAPK signaling pathways were correlated with sensitivity to CCI-779. Resistant cells with increased EGFR activation could be sensitized by the combination of CCI-779 with cetuximab. Interestingly, cell lines with acquired resistance to cisplatin displayed a higher sensitivity to CCI-779 whereas cetuximab-resistant cells were less sensitive to the drug, but could be sensitized to CCI-779 by EGFR blockade.
  
  
  CONCLUSIONS
  Activity of CCI-779 in HNSCC cells harboring TP53 mutations and displaying a phenotype of cisplatin resistance suggests its clinical potential even in patients with dismal outcome after current standard treatment. Cetuximab/mTORi combinations might be useful for treatment of tumors with high expression of EGFR/p-EGFR and/or acquired cetuximab resistance. This combinatorial treatment modality needs further evaluation in future translational and clinical studies.
authors.affiliation: Translational Radiooncology Laboratory, Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany. franziska.niehr@charite.de.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Partner Site Berlin, Berlin, Germany. franziska.niehr@charite.de.
authors.forename: Franziska
authors.initials: F
authors.lastname: Niehr
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. Wilko.Weichert@med.uni-heidelberg.de.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Partner Site Heidelberg, Heidelberg, Germany. Wilko.Weichert@med.uni-heidelberg.de.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. Albrecht.Stenzinger@med.uni-heidelberg.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: Translational Radiooncology Laboratory, Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany. volker.budach@charite.de.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Partner Site Berlin, Berlin, Germany. volker.budach@charite.de.
authors.forename: Volker
authors.initials: V
authors.lastname: Budach
authors.affiliation: Translational Radiooncology Laboratory, Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany. ingeborg.tinhofer@charite.de.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Partner Site Berlin, Berlin, Germany. ingeborg.tinhofer@charite.de.|Department of Radiooncology and Radiotherapy, Translational Radiooncology Laboratory, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany. ingeborg.tinhofer@charite.de.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Tinhofer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology* / Q000627:therapeutic use; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D009154:Mutation / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; C401859:temsirolimus; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D000068818:Cetuximab; D002945:Cisplatin; D020123:Sirolimus