Targeting Interleukin-6 as a Novel Strategy to Overcome Eribulin Resistance in Breast Cancer.

BACKGROUND: In breast cancer, elevated serum interleukin-6 (IL-6) level is associated with a poor prognosis during eribulin treatment; however, the mechanisms underlying IL-6-mediated resistance and its potential as a therapeutic target remain unclear. We aimed to determine whether IL-6 is involved in eribulin resistance and evaluate the therapeutic potential of combining eribulin with an IL-6 receptor-specific inhibitor to overcome resistance. METHODS: Eribulin-resistant cell lines (MCF-7E and MDA-MB-231E) were established through prolonged culture with eribulin. IL-6 in conditioned media was quantified using enzyme-linked immunosorbent assay, and RNA-seq was performed to identify pathways associated with eribulin resistance. The therapeutic efficacy of eribulin in combination with tocilizumab (TCZ), an IL-6 receptor inhibitor, was assessed using a patient-derived xenograft (PDX) mouse model with acquired eribulin resistance. RESULTS: The IC50 of eribulin in both MCF-7E and MDA-MB-231E cells was > 500-fold higher than that of their parental counterparts. RNA-seq revealed significant activation of several signaling pathways, particularly the IL-6-JAK-STAT pathway, in eribulin-resistant cells but not in doxorubicin-resistant MCF-7D cells. Gene set enrichment analysis confirmed the enrichment of IL-6-JAK-STAT pathway-related genes in MCF-7E and MDA-MB-231E. Although TCZ alone had no effect on cell viability, its combination with eribulin had a synergistic inhibitory effect on MDA-MB-231 cells. In the PDX model, tumor growth in the eribulin + TCZ group was significantly suppressed compared with that in the eribulin-only group. CONCLUSIONS: These findings suggest that IL-6 contributes to eribulin resistance in breast cancer and that IL-6 receptor inhibition is a promising therapeutic strategy to overcome this resistance.