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<p>Ewing sarcoma (EWS) is a highly aggressive pediatric malignancy characterized by elevated expression of <i>SLFN11</i>, which impairs DNA repair by binding to and functionally inhibiting DNA repair complexes, thereby enhancing susceptibility to genotoxic therapies. However, relapse remains a major clinical challenge and is often accompanied by the emergence of therapeutic resistance linked to reduced <i>SLFN11</i> expression. We hypothesized that <i>SLFN11</i>-deficient tumors undergo adaptive metabolic reprogramming to overcome chemosensitivity. Here, we leverage transcriptomic and metabolomic profiling in patient-derived EWS models to demonstrate that <i>SLFN11</i> loss drives downregulated mitochondrial glycerol-3-phosphate dehydrogenase (<i>GPD2</i>) expression, higher accumulation of glycerol-3-phosphate, fatty acid unsaturation, and enhanced glycerophospholipid (GPL) biosynthesis. Subsequently, targeting GPL biosynthesis (FSG67) restored DNA-damaging agent (SN-38) sensitivity in <i>SLFN11</i>-deficient EWS model, revealing a potential metabolic vulnerability to overcome chemoresistance. Furthermore, <i>SLFN11</i> knockout tumors exhibited an elevated phosphocholine/glycerophosphocholine ratio, offering a potential non-invasive diagnostic biomarker.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月31日

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  • Kasturee Chakraborty,
  • Ritambhar Burman,
  • Saharsh Satheesh,
  • Matthew Kieffer,
  • Chandni Karuhatty,
  • Zuo-Fei Yuan,
  • Haiyan Tan,
  • Ankhbayar Lkhagva,
  • Anthony A. High,
  • Xusheng Wang,
  • Alaa Refaat,
  • Nathaniel R. Twarog,
  • Weixing Zhang,
  • Yaxu Wang,
  • Yiping Fan,
  • Qian Li,
  • M. Madan Babu,
  • Anang A. Shelat,
  • Elizabeth Stewart,
  • Michael A. Dyer,
  • Puneet Bagga

摘要

Ewing sarcoma (EWS) is a highly aggressive pediatric malignancy characterized by elevated expression of SLFN11, which impairs DNA repair by binding to and functionally inhibiting DNA repair complexes, thereby enhancing susceptibility to genotoxic therapies. However, relapse remains a major clinical challenge and is often accompanied by the emergence of therapeutic resistance linked to reduced SLFN11 expression. We hypothesized that SLFN11-deficient tumors undergo adaptive metabolic reprogramming to overcome chemosensitivity. Here, we leverage transcriptomic and metabolomic profiling in patient-derived EWS models to demonstrate that SLFN11 loss drives downregulated mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) expression, higher accumulation of glycerol-3-phosphate, fatty acid unsaturation, and enhanced glycerophospholipid (GPL) biosynthesis. Subsequently, targeting GPL biosynthesis (FSG67) restored DNA-damaging agent (SN-38) sensitivity in SLFN11-deficient EWS model, revealing a potential metabolic vulnerability to overcome chemoresistance. Furthermore, SLFN11 knockout tumors exhibited an elevated phosphocholine/glycerophosphocholine ratio, offering a potential non-invasive diagnostic biomarker.