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<p>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<sup>CRR</sup>) displayed enhanced cancer stem cell features, evasion of RT-induced G2/M arrest, and reduced apoptosis compared to their parental counterparts (RMS<sup>PR</sup>). 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<sup>CRR</sup> <i>versus</i> FP-RMS<sup>CRR</sup> 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<sup>PR</sup> and RMS<sup>CRR</sup> cells. In vivo, RT and TZM co-treatment fully suppressed FN-RMS<sup>PR</sup> tumor growth and delayed FP-RMS<sup>PR</sup> progression. Notably, TZM monotherapy inhibited tumor growth in both FN- and FP-RMS<sup>CRR</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月1日

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  • Matteo Cassandri,
  • Antonella Porrazzo,
  • Simona Camero,
  • Silvia Pomella,
  • Valeria Manzi,
  • Francesca Vulcano,
  • Luisa Milazzo,
  • Francesca Pedini,
  • Deborah Pajalunga,
  • Andrea Casagrande,
  • Giada Mele,
  • Valentina Lulli,
  • Enrico Romano,
  • Michele Signore,
  • Massimo Spada,
  • Maria Teresa D’Urso,
  • Silvia Codenotti,
  • Alessandro Fanzani,
  • Annunziata Mauro,
  • Giovanna Marchese,
  • Simone Sidoli,
  • Giovanni Luca Gravina,
  • Giovanni Barillari,
  • Franco Locatelli,
  • Francesca Megiorni,
  • Rossella Rota,
  • Francesco Marampon

摘要

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 (RMSCRR) displayed enhanced cancer stem cell features, evasion of RT-induced G2/M arrest, and reduced apoptosis compared to their parental counterparts (RMSPR). 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-RMSCRR versus FP-RMSCRR 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 RMSPR and RMSCRR cells. In vivo, RT and TZM co-treatment fully suppressed FN-RMSPR tumor growth and delayed FP-RMSPR progression. Notably, TZM monotherapy inhibited tumor growth in both FN- and FP-RMSCRR 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.