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PAX3-FOXO1 Drives Targetable Cell State-Dependent Metabolic Vulnerabilities in Rhabdomyosarcoma.

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|September 5, 2025
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Summary
This summary is machine-generated.

Aggressive rhabdomyosarcoma (RMS) driven by PAX3-FOXO1 shows increased reliance on pyrimidine synthesis. Targeting dihydrofolate reductase (DHFR) with methotrexate offers a potential new therapy for these pediatric tumors.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • PAX3-FOXO1 is a key driver of aggressive rhabdomyosarcoma (RMS).
  • Malignant cells often exhibit altered metabolic pathways to support rapid growth.
  • Understanding the specific metabolic dependencies of RMS subtypes is crucial for targeted therapy.

Purpose of the Study:

  • To investigate the metabolic alterations in PAX3-FOXO1-driven RMS.
  • To identify potential therapeutic vulnerabilities associated with these metabolic changes.
  • To evaluate the efficacy of targeting pyrimidine synthesis in PAX3-FOXO1+ RMS.

Main Methods:

  • Analysis of gene expression and metabolic pathways in PAX3-FOXO1+ RMS cells.
  • Assessment of cellular sensitivity to dihydrofolate reductase (DHFR) inhibition using methotrexate.
  • Rescue experiments with pyrimidine nucleotides.
  • In vivo studies using PAX3-FOXO1+ and fusion-negative RMS xenograft models.

Main Results:

  • PAX3-FOXO1+ RMS cells display altered pyrimidine metabolism with increased dependence on de novo synthesis, including DHFR.
  • These cells are sensitive to DHFR inhibition by methotrexate, a sensitivity that can be rescued by pyrimidine nucleotides.
  • Methotrexate treatment recapitulates the metabolic and transcriptional effects of PAX3-FOXO1 silencing.
  • Methotrexate significantly slowed tumor growth in PAX3-FOXO1+ RMS xenografts but not in fusion-negative RMS.

Conclusions:

  • PAX3-FOXO1 oncogenic factor induces a state of pyrimidine dependence in RMS.
  • DHFR inhibition via methotrexate represents a promising therapeutic strategy for PAX3-FOXO1-driven rhabdomyosarcoma.
  • Methotrexate could be a valuable addition to the treatment regimen for these aggressive pediatric tumors.