# Targeting glycerophospholipid biosynthesis overcomes chemoresistance driven by SLFN11 loss in Ewing sarcoma **Authors:** 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 PMC · DOI: 10.1038/s41419-026-08432-7 · Cell Death & Disease · 2026-01-31 ## TL;DR This study shows that targeting glycerophospholipid biosynthesis can overcome chemotherapy resistance in Ewing sarcoma when SLFN11 levels are low. ## Contribution The study identifies a novel metabolic vulnerability in SLFN11-deficient Ewing sarcoma and proposes a potential non-invasive biomarker for chemoresistance. ## Key findings - SLFN11 loss in Ewing sarcoma leads to increased glycerophospholipid biosynthesis and fatty acid unsaturation. - Targeting glycerophospholipid biosynthesis with FSG67 restores chemotherapy sensitivity in SLFN11-deficient models. - An elevated phosphocholine/glycerophosphocholine ratio in SLFN11-deficient tumors may serve as a non-invasive biomarker. ## Abstract 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. ## Linked entities - **Genes:** SLFN11 (schlafen family member 11) [NCBI Gene 91607], GPD2 (glycerol-3-phosphate dehydrogenase 2) [NCBI Gene 2820] - **Chemicals:** SN-38 (PubChem CID 104842), FSG67 (PubChem CID 44139871), glycerol-3-phosphate (PubChem CID 754), phosphocholine (PubChem CID 1014), glycerophosphocholine (PubChem CID 11234) - **Diseases:** Ewing sarcoma (MONDO:0012817) ## Full-text entities - **Genes:** SCD (stearoyl-CoA desaturase) [NCBI Gene 6319] {aka FADS5, MSTP008, SCD1, SCDOS, hSCD1}, GPD1L (glycerol-3-phosphate dehydrogenase 1 like) [NCBI Gene 23171] {aka GPD1-L}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, GPD1 (glycerol-3-phosphate dehydrogenase 1) [NCBI Gene 2819] {aka GPD-C, GPDH-C, HTGTI}, DDB1 (damage specific DNA binding protein 1) [NCBI Gene 1642] {aka DDBA, UV-DDB1, WHIKERS, XAP1, XPCE, XPE}, COL11A2 (collagen type XI alpha 2 chain) [NCBI Gene 1302] {aka DFNA13, DFNB53, FBCG2, HKE5, OSMEDA, OSMEDB}, EWSR1 (EWS RNA binding protein 1) [NCBI Gene 2130] {aka EWS, EWS-FLI1}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, SLFN11 (schlafen family member 11) [NCBI Gene 91607] {aka SLFN8/9}, AGPAT4 (1-acylglycerol-3-phosphate O-acyltransferase 4) [NCBI Gene 56895] {aka 1-AGPAT4, LPAAT-delta, LPAAT4, LPLAT4, dJ473J16.2}, GPAM (glycerol-3-phosphate acyltransferase, mitochondrial) [NCBI Gene 57678] {aka GPAT, GPAT1}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, FASN (fatty acid synthase) [NCBI Gene 2194] {aka FAS, OA-519, SDR27X1}, Ewsr1 (Ewing sarcoma breakpoint region 1) [NCBI Gene 14030] {aka Ews, Ewsh}, ERG (ETS transcription factor ERG) [NCBI Gene 2078] {aka LMPHM14, erg-3, p55}, PCNA (proliferating cell nuclear antigen) [NCBI Gene 5111] {aka ATLD2}, ACACA (acetyl-CoA carboxylase alpha) [NCBI Gene 31] {aka ACAC, ACACAD, ACACalpha, ACC, ACC1, ACCA}, CMPK1 (cytidine/uridine monophosphate kinase 1) [NCBI Gene 51727] {aka CK, CMK, CMPK, UMK, UMP-CMPK, UMPK}, RPA1 (replication protein A1) [NCBI Gene 6117] {aka HSSB, MST075, PFBMFT6, REPA1, RF-A, RP-A}, EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) [NCBI Gene 2146] {aka ENX-1, ENX1, EZH2b, KMT6, KMT6A, WVS}, SREBF1 (sterol regulatory element binding transcription factor 1) [NCBI Gene 6720] {aka HMD, IFAP2, SREBP1, bHLHd1}, IL31RA (interleukin 31 receptor A) [NCBI Gene 133396] {aka CRL, CRL3, GLM-R, GLMR, GPL, IL-31RA}, FLI1 (Fli-1 proto-oncogene, ETS transcription factor) [NCBI Gene 2313] {aka BDPLT21, EWSR2, FLI-1, SIC-1}, MYC (MYC proto-oncogene, bHLH transcription factor) [NCBI Gene 4609] {aka MRTL, MYCC, bHLHe39, c-Myc}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, BLNK (B cell linker) [NCBI Gene 29760] {aka AGM4, BASH, BLNK-S, LY57, SLP-65, SLP65}, GYPC (glycophorin C (Gerbich blood group)) [NCBI Gene 2995] {aka CD236, CD236R, GE, GPC, GPD, GYPD}, CDT1 (chromatin licensing and DNA replication factor 1) [NCBI Gene 81620] {aka DUP, RIS2}, CDC45 (cell division cycle 45) [NCBI Gene 8318] {aka CDC45L, CDC45L2, MGORS7, PORC-PI-1}, GPD2 (glycerol-3-phosphate dehydrogenase 2) [NCBI Gene 2820] {aka GDH2, GPDM, mGDH, mGPDH}, ATR (ATR checkpoint kinase) [NCBI Gene 545] {aka FCTCS, FRP1, MEC1, SCKL, SCKL1}, TXK (TXK tyrosine kinase) [NCBI Gene 7294] {aka BTKL, PSCTK5, PTK4, RLK, TKL}, MCM3 (minichromosome maintenance complex component 3) [NCBI Gene 4172] {aka HCC5, P1-MCM3, P1.h, RLFB}, POTEF (POTE ankyrin domain family member F) [NCBI Gene 728378] {aka A26C1B, POTE2alpha, POTEACTIN} - **Diseases:** tumorigenesis (MESH:D063646), breast cancer (MESH:D001943), inflammatory (MESH:D007249), colorectal cancer (MESH:D015179), renal cell carcinoma (MESH:D002292), G3PS (MESH:C536837), acute myeloid leukemia (MESH:D015470), weight loss (MESH:D015431), prostate cancer (MESH:D011471), gastric cancer (MESH:D013274), cytotoxic (MESH:D064420), EWS (MESH:D012512), lung cancer (MESH:D008175), hepatocellular carcinoma (MESH:D006528), ovarian cancer (MESH:D010051), Cancer (MESH:D009369), PC (MESH:C535298), neuroblastoma (MESH:D009447), NSCLC (MESH:D002289), aggressiveness (MESH:D010554), glioblastoma (MESH:D005909), kidney cancer (MESH:D007680), small cell lung cancer (MESH:D055752), medulloblastoma (MESH:D008527) - **Chemicals:** H2O (MESH:D014867), PA (MESH:D010712), ammonium acetate (MESH:C018824), O-Phosphoethanolamine (MESH:C005448), G3P (MESH:C029620), triacylglycerol (MESH:D014280), gemcitabine (MESH:D000093542), SN-38 (MESH:D000077146), palmitate (MESH:D010168), GPL (MESH:D020404), oleate (MESH:D019301), membrane lipid (MESH:D008563), ifosfamide (MESH:D007069), CO2 (MESH:D002245), TCA (MESH:D014233), phospholipid (MESH:D010743), acetyl-CoA (MESH:D000105), Cho (MESH:C034482), PC (MESH:D010713), phosphatidylserine (MESH:D010718), regorafenib (MESH:C559147), topotecan (MESH:D019772), PVDF (MESH:C024865), ethanolamine (MESH:D019856), temozolomide (MESH:D000077204), lenvatinib (MESH:C531958), serine (MESH:D012694), streptomycin (MESH:D013307), ethanol (MESH:D000431), DMSO (MESH:D004121), unsaturated fatty acid (MESH:D005231), cabozantinib (MESH:C558660), docetaxel (MESH:D000077143), phosphate (MESH:D010710), CDP ethanolamine (MESH:C006933), DAG (MESH:D004075), carbon (MESH:D002244), cardiolipin (MESH:D002308), penicillin (MESH:D010406), DHAP (MESH:D004099), Acetate (MESH:D000085), purine (MESH:C030985), MUFAs (MESH:D005229), 13C (MESH:C000615229), D2O (MESH:D017666), acetonitrile (MESH:C032159), DDAs (MESH:C000849), G3PS (-), isopropanol (MESH:D019840), PG (MESH:D010715), Gln (MESH:D005973), McCoy's 5A medium (MESH:C113109), PE (MESH:C483858), PCh (MESH:D010767), PI (MESH:D010716), methanol (MESH:D000432), CDP-choline (MESH:D003566), Glucose (MESH:D005947), HCl (MESH:D006851), formic acid (MESH:C030544) - **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090] - **Cell lines:** EW-8 — Homo sapiens (Human), Ewing sarcoma, Cancer cell line (CVCL_1658), SK ES-1 — Homo sapiens (Human), Ewing sarcoma, Cancer cell line (CVCL_0627), S2f — Drosophila melanogaster (Fruit fly), Spontaneously immortalized cell line (CVCL_A5UZ), ES-8 — Homo sapiens (Human), Embryonic stem cell (CVCL_C775), S2e — Opodiphthera eucalypti (Emperor gum moth), Spontaneously immortalized cell line (CVCL_Z109), CADO ES-1 — Homo sapiens (Human), Ewing sarcoma, Cancer cell line (CVCL_1103), RD ES-1 — Homo sapiens (Human), Ewing sarcoma, Cancer cell line (CVCL_2169), SK ES-1 WT — Mus musculus (Mouse), Transformed cell line (CVCL_VU16), ES-8 WT — Homo sapiens (Human), Transformed cell line (CVCL_E889), S2 — Drosophila melanogaster (Fruit fly), Spontaneously immortalized cell line (CVCL_Z232) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12877146/full.md ## Figures 6 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12877146/full.md ## References 6 references — full list in the complete paper: https://tomesphere.com/paper/PMC12877146/full.md --- Source: https://tomesphere.com/paper/PMC12877146