title: Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer.
abstract: BACKGROUND
  Interleukin-6 (IL-6) can activate downstream signaling pathways in lung cancer cells, such as the STAT3 pathway, and is reported to be produced by tumor cells with activating EGFR mutations. We examined IL-6/STAT3 in lung cancer tumor tissues and the effects of siltuximab, a neutralizing antibody to human IL-6, in mouse models of lung cancer.
  
  
  METHODS
  IL-6 and STAT3 activation levels were compared with tumor histology and presence of KRAS mutations in snap-frozen, non-small-cell lung cancer tumors. The effects of siltuximab alone or in combination with erlotinib were examined in mouse xenograft models constructed using three cell line xenograft models and one primary explant mouse model. We examined the influence of cancer-associated fibroblasts (CAFs) on tumor growth and siltuximab effects.
  
  
  RESULTS
  IL-6 levels were higher in tumors of squamous cell versus adenocarcinoma histology and were not associated with presence of KRAS mutations. Tyrosine phosphorylation status of STAT3 did not correlate with tumor IL-6 levels. Serine phosphorylation of STAT3 was correlated with KRAS mutation status. Both tumor and stromal cells contributed to total IL-6 within tumors. Siltuximab had minimal effect as a single agent in xenografts with tumor cells alone; however, in models coadministered with CAFs, siltuximab had more potent effects on tumor inhibition. We observed no effects of combined erlotinib and siltuximab.
  
  
  CONCLUSIONS
  IL-6 is elevated in subsets of human NSCLCs, especially with squamous cell histology. Tumors supported by stromal production of IL-6 seem to be the most vulnerable to tumor growth inhibition by siltuximab.
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Lanxi
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Janssen R&D, Spring House, PA.
authors.forename: Parul
authors.initials: P
authors.lastname: Doshi
authors.affiliation: Janssen R&D, Spring House, PA.
authors.forename: Kate
authors.initials: K
authors.lastname: Sasser
authors.affiliation: Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: William
authors.initials: W
authors.lastname: Fulp
authors.affiliation: Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Soner
authors.initials: S
authors.lastname: Altiok
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. Electronic address: Eric.haura@moffitt.org.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000069347:Erlotinib Hydrochloride; D005260:Female; D005347:Fibroblasts; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis / Q000276:immunology; D008175:Lung Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015850:Interleukin-6; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014443:Tyrosine; D012694:Serine; D000069347:Erlotinib Hydrochloride; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C504234:siltuximab