What question did this study set out to answer?

Identify the molecular basis of radioresistance in rhabdomyosarcoma and evaluate the therapeutic potential of Tazemetostat.

June 3, 2026Open Access

Multi-omics analyses identify EZH2 as a central driver in rhabdomyosarcoma radioresistance and highlight Tazemetostat as an effective radiosensitizer in vitro and in vivo

MCMatteo CassandriBambino Gesù Children's Hospital APAntonella PorrazzoPoliclinico Umberto I SCSimona CameroLink Campus University

Key Points

Identify the molecular basis of radioresistance in rhabdomyosarcoma and evaluate the therapeutic potential of Tazemetostat.
Utilized an integrative multi-omics approach including phosphoproteomics and transcriptomics.
Analyzed radioresistant and parental RMS cell models for differences in signalling pathways and gene expression.
Conducted in vivo experiments to assess tumor growth following radiotherapy with Tazemetostat co-treatment.
EZH2-driving signaling was hyperactive in radioresistant RMS models, with reduced apoptosis and evasion of G2/M arrest.
Tazemetostat significantly reduced clonogenic survival and enhanced cell death in both RMS subtypes during radiotherapy.
In vivo, Tazemetostat and radiotherapy together suppressed tumor growth in FN-RMS models and delayed FP-RMS progression.

Abstract

Abstract Rhabdomyosarcoma (RMS), a pediatric soft tissue sarcoma, comprises two major subtypes: fusion-positive (FP), driven by PAX3/7-FOXO1 fusions, and fusion-negative (FN), often harboring RAS pathway mutations. High-risk RMS exhibits intrinsic resistance to radiotherapy (RT), posing a significant clinical hurdle. Emerging evidence implicates EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), in promoting RT resistance through gene silencing via H3K27me3. To dissect the molecular basis of RMS radioresistance, we employed an integrative multi-omics approach encompassing phosphoproteomics and transcriptomics. Radioresistant RMS cell models (RMS CRR ) displayed enhanced cancer stem cell features, evasion of RT-induced G2/M arrest, and reduced apoptosis compared to their parental counterparts (RMS PR ). Phosphoproteomic profiling revealed activation of prosurvival and proliferative pathways across both FN and FP subtypes. Transcriptomic analysis identified a robust downregulation of EZH2 target genes, with distinct gene sets modulated in FN-RMS CRR versus FP-RMS CRR cells, highlighting subtype-specific epigenetic rewiring. These multi-omics findings pointed to hyperactive PRC2/EZH2 signaling as a driver of radioresistance. Therapeutically, combining the EZH2 inhibitor Tazemetostat (TZM) with RT significantly impaired clonogenic survival, enhanced G2/M arrest, and promoted apoptosis in both RMS PR and RMS CRR cells. In vivo, RT and TZM co-treatment fully suppressed FN-RMS PR tumor growth and delayed FP-RMS PR progression. Notably, TZM monotherapy inhibited tumor growth in both FN- and FP-RMS CRR xenografts, uncovering a therapy-induced vulnerability. Our integrative multi-omics analysis reveals EZH2-dependent molecular programs underpinning radioresistance and supports EZH2 targeting as a rational radiosensitizing and therapeutic strategy in RMS, including recurrent and RT-refractory disease.

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