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Targeting glycerophospholipid biosynthesis overcomes chemoresistance driven by SLFN11 loss in Ewing sarcoma

Kasturee Chakraborty1, Ritambhar Burman1, Saharsh Satheesh1

  • 1Department of Radiology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Cell Death & Disease
|January 31, 2026
PubMed

Insights

Reduced SLFN11 expression in Ewing sarcoma (EWS) causes metabolic changes, leading to chemoresistance. Targeting glycerophospholipid biosynthesis can restore sensitivity, offering a new therapeutic strategy for EWS.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Research

Background:

  • Ewing sarcoma (EWS) is an aggressive pediatric cancer.
  • SLFN11 expression enhances sensitivity to genotoxic therapies.
  • Therapeutic resistance in EWS is linked to reduced SLFN11 expression.

Purpose of the Study:

  • To investigate the metabolic reprogramming in SLFN11-deficient EWS tumors.
  • To identify metabolic vulnerabilities that can overcome chemoresistance in EWS.
  • To explore potential non-invasive diagnostic biomarkers for EWS.

Main Methods:

  • Transcriptomic and metabolomic profiling of patient-derived EWS models.
  • Analysis of glycerol-3-phosphate dehydrogenase (GPD2) expression and glycerol-3-phosphate accumulation.
  • Assessment of fatty acid unsaturation and glycerophospholipid (GPL) biosynthesis.
  • Evaluation of therapeutic agents targeting GPL biosynthesis (FSG67) and DNA-damaging agents (SN-38).

Main Results:

  • SLFN11 loss downregulated GPD2 expression, increased glycerol-3-phosphate, enhanced fatty acid unsaturation, and boosted GPL biosynthesis.
  • Targeting GPL biosynthesis with FSG67 restored SN-38 sensitivity in SLFN11-deficient EWS models.
  • SLFN11 knockout tumors showed an elevated phosphocholine/glycerophosphocholine ratio.

Conclusions:

  • SLFN11-deficient EWS tumors exhibit metabolic reprogramming characterized by enhanced GPL biosynthesis, contributing to chemoresistance.
  • Targeting GPL biosynthesis represents a potential strategy to overcome chemoresistance in EWS.
  • The phosphocholine/glycerophosphocholine ratio may serve as a non-invasive diagnostic biomarker for EWS.

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