Antitumor efficacy of the anti-interleukin-6 (IL-6) antibody siltuximab in mouse xenograft models of lung cancer.

Abstract

INTRODUCTION:

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: Lanxi Song, Matthew A Smith, Parul Doshi, Kate Sasser, William Fulp, Soner Altiok, Eric B Haura
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 9 Issue 7 Pg. 974-982 (Jul 2014) ISSN: 1556-1380 [Electronic] United States
• PMID: 24922005 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Interleukin-6
• KRAS protein, human
• Proto-Oncogene Proteins
• Quinazolines
• STAT3 Transcription Factor
• STAT3 protein, human
• Tyrosine
• Serine
• Erlotinib Hydrochloride
• Proto-Oncogene Proteins p21(ras)
• ras Proteins
• siltuximab

Topics

• Adenocarcinoma (chemistry, drug therapy, genetics)
• Animals
• Antibodies, Monoclonal (administration & dosage, therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (chemistry, drug therapy, genetics)
• Carcinoma, Squamous Cell (chemistry, drug therapy, genetics)
• Cell Line, Tumor
• Disease Models, Animal
• Erlotinib Hydrochloride
• Female
• Fibroblasts
• Humans
• Interleukin-6 (analysis, immunology)
• Lung Neoplasms (chemistry, drug therapy, genetics)
• Mice
• Phosphorylation
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Quinazolines (administration & dosage)
• STAT3 Transcription Factor (metabolism)
• Serine (metabolism)
• Tyrosine (metabolism)
• ras Proteins (genetics)