# Striking at Survivin: YM-155 Inhibits High-Risk Neuroblastoma Growth and Enhances Chemosensitivity

## TL;DR

This study shows that the drug YM-155 can effectively target the protein survivin in high-risk neuroblastoma, reducing tumor growth and improving response to chemotherapy.

## Contribution

The study demonstrates that YM-155, a survivin inhibitor, is a promising new therapeutic option for high-risk neuroblastoma.

## Key findings

- YM-155 significantly reduced tumor burden in a mouse model without toxicity.
- YM-155 synergized with etoposide to enhance NB growth inhibition.
- High BIRC5 expression in NB patients correlates with reduced survival.

## Abstract

Neuroblastoma (NB) remains one of the most aggressive pediatric cancers, with high-risk disease showing poor prognosis and limited therapeutic options. Survivin (BIRC5), an anti-apoptotic protein frequently overexpressed in NB, is associated with resistance and adverse clinical outcomes. Analysis of NB patient datasets confirmed that high BIRC5 expression correlates with reduced survival. To investigate survivin targeting, we evaluated YM-155, a small-molecule inhibitor, in NB models. YM-155 demonstrated potent cytotoxicity, suppressed colony formation and 3D spheroid growth, downregulated survivin, induced apoptosis, and caused G0/G1 cell cycle arrest. Combination of YM-155 with etoposide produced synergistic activity, and in vivo YM-155 significantly reduced tumor burden without observed toxicity. These findings establish YM-155 as a promising therapeutic candidate and support survivin inhibition as a rational strategy in NB.

Background/Objectives: Neuroblastoma (NB) is an aggressive pediatric malignancy that accounts for nearly 15% of all childhood cancer-related deaths, with high-risk cases showing a poor 20% prognosis and limited response to current therapies. Survivin, encoded by the BIRC5 gene, is an anti-apoptotic protein frequently overexpressed in NB and linked to treatment resistance and unfavorable clinical outcomes. Methods and Results: An analysis of 1235 NB patient datasets revealed a significant association between elevated BIRC5 expression and reduced overall and event-free survival, highlighting survivin as an important therapeutic target in NB. To explore this strategy, we evaluated the efficacy of YM-155, a small-molecule survivin inhibitor, across multiple NB cell lines. YM-155 displayed potent cytotoxic activity in six NB cell lines with IC50 values ranging from 8 to 212 nM and significantly inhibited colony formation and 3D spheroid growth in a dose-dependent manner. Mechanistic analyses revealed that YM-155 downregulated survivin at both mRNA and protein levels, induced apoptosis by about 2–7-fold, and caused G0/G1 phase cell cycle arrest. Moreover, YM-155 treatment enhanced p53 expression, suggesting reactivation of tumor suppressor pathways. Notably, combining YM-155 and the chemotherapeutic agent etoposide resulted in synergistic inhibition of NB growth with ED75 values ranging from 0.17 to 1, compared to either agent alone. In the xenograft mouse model, YM-155 inhibited tumor burden in contrast to controls by about 3-fold, and without any notable toxic effects in vivo. Conclusion: Overall, our findings identify YM-155 as a promising therapeutic agent for high-risk NB by directly targeting survivin and enhancing chemosensitivity. These results support continued preclinical development of survivin inhibitors as part of rational combination strategies in pediatric cancer treatment.