# Targeting Interleukin‐6 as a Novel Strategy to Overcome Eribulin Resistance in Breast Cancer

## TL;DR

This study shows that blocking IL-6 can help overcome resistance to eribulin, a breast cancer drug, offering a new treatment strategy.

## Contribution

The paper introduces IL-6 receptor inhibition as a novel approach to counter eribulin resistance in breast cancer.

## Key findings

- Eribulin-resistant cells showed significant activation of the IL-6–JAK–STAT pathway.
- Combining eribulin with an IL-6 receptor inhibitor synergistically reduced cancer cell viability.
- In a PDX model, the combination therapy significantly suppressed tumor growth compared to eribulin alone.

## Abstract

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.

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.

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.

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.