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.